Diaminopyridine-containing thiourea inhibitors of herpes viruses

ABSTRACT

Compounds of the formula  
                 
 
     R 1 -R 5  are independently selected from hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, perhaloalkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, heterocycloalkyl of 3 to 10 carbon members, aryl, heteroaryl, halogen, —CN, —NO 2 , —CO 2 R 6 , —COR 6 , —OR 6 , —SR 6 , —SOR 6 , —SO 2 R 6 , —CONR 7 R 8 , —NR 6 N(R 7 R 8 ), —(R 7 R 8 ) or W—Y—(CH 2 )—Z; or R 2  and R 3  or R 3  and R 4 , taken together form a 3 to 7 membered heterocycloalkyl or 3 to 7 membered heteroaryl;  
     R 6  and R 7  are independently hydrogen, alkyl of 1 to 6 carbon atoms, perhaloalkyl of 1 to 6 carbon atoms, or aryl;  
     R 8  is hydrogen, alkyl of 1 to 6 carbon atoms, perhaloalkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, heterocycloalkyl of 3 to 10 members, aryl or heteroaryl, or  
     R 7  and R 8 , taken together may form a 3 to 7 membered heterocycloalkyl;  
     A is heteroaryl;

[0001] This application claims the benefit of U.S. ProvisionalApplication Nos. 60/150,698, 60/155,240, 60/155,192, and 60/150,692, andU.S. application Ser. Nos. 09/208,540, 09/208,164, 09/208,561 each ofwhich was filed Dec. 9, 1998. These applications are herein incorporatedby reference in their entireties.

BACKGROUND OF THE INVENTION

[0002] Eight viruses have been identified which are members of thefamily Herpesviridae (reviewed in Roizman, B. 1996. Herpesviridae, p.2221-2230. In B. N. Fields, D. M. Knipe, and P. M. Howley (ed.), FieldsVirology, 3rd ed. Lippincott-Raven Publishers, Philadelphia, Pa.). Eachmember of this family is characterized by an enveloped virus containingproteinaceous tegument and nucleocapsid, the latter of which houses theviruses' relatively large double-stranded DNA genome (i.e. approximately80-250 kilobases). Members of the human alphaherpesvirus subfamily areneurotropic and include herpes simplex virus type 1 (HSV-1) and type 2(HSV-2), and varicella-zoster virus (VZV). The human betaherpesvirusesare cytomegalovirus (HCMV), human herpesvirus 6 (HHV-6) and humanherpesvirus 7 (HHV-7). The gammaherpesviruses are lymphotropic andinclude Epstein-Barr virus (EBV) and Kaposi's herpesvirus (HHV-8). Eachof these herpesviruses is causally-related to human disease, includingherpes labialis and herpes genitalis (HSV-1 and HSV-2 [Whitley, R. J.1996. Herpes Simplex Viruses, p. 2297-2342. In B. N. Fields, D. M.Knipe, and P. M. Howley (ed.), Fields Virology, 3rd ed. Lippincott-RavenPublishers, Philadelphia, Pa.]); chicken pox and shingles (VZV [Arvin,A. 1996. Varicella-Zoster Virus, p. 2547-2585. In B. N. Fields, D. M.Knipe, and P. M. Howley (ed.), Fields Virology, 3rd ed. Lippincott-RavenPublishers, Philadelphia, Pa.]); infectious mononucleosis (EBV[Rickinson, A. B. and Kieff, E. 1996. Epstein-Barr Virus, p. 2397-2446.In B. N. Fields, D. M. Knipe, and P. M. Howley (ed.), Fields Virology,3rd ed. Lippincott-Raven Publishers, Philadelphia, Pa.]); pneumonia andretinitis (HCMV [(Britt, W. J., and Alford, C. A. 1996. Cytomegalovirus,p. 2493-2523. In B. N. Fields, D. M. Knipe, and P. M. Howley (ed.),Fields Virology, 3rd ed. Lippincott-Raven Publishers, Philadelphia,Pa.]); exanthem subitum (HHV-6 [(Pellet, P. E, and Black, J. B. 1996.Human Herpesvirus 6, p. 2587-2608. In B. N. Fields, D. M. Knipe, and P.M. Howley (ed.), Fields Virology, 3rd ed. Lippincott-Raven Publishers,Philadelphia, PA] and HHV-7 [Frenkel, N., and Roffman, E. 1996. HumanHerpesvirus 7, p. 2609-2622. In B. N. Fields, D. M. Knipe, and P. M.Howley (ed.), Fields Virology, 3rd ed. Lippincott-Raven Publishers,Philadelphia, Pa.]); and Kaposi's sarcoma (HHV-8 [Neipel, F., Albrecht,J. C., and Fleckenstein, B. 1997. Cell-homologous genes in the Kaposi'ssarcoma-associated rhadinovirus human herpesvirus 8: determinants of itspathogenicity? J. Virol. 71:4187-92, 1997]). HCMV is considered in moredetail below. Following the primary infection, herpesviruses establishlatency within the infected individual and remain there for theremainder of his/her life. Periodic reactivation of latent virus isclinically relevant. In the case of HSV, reactivated virus can betransmitted to infants during birth, causing either skin or eyeinfection, central nervous system infection, or disseminated infection(i.e. multiple organs or systems). Shingles is the clinicalmanifestation of VZV reactivation. Treatment of HSV and VZV is generallywith antiviral drugs such as acyclovir (Glaxo Wellcome), ganciclovir(Roche) and foscarnet (Asta) which target viral encoded DNA polymerase.

[0003] HCMV is a ubiquitous opportunistic pathogen infecting 50-90% ofthe adult population (Britt, W. J., and Alford, C. A. 1996.Cytomegalovirus, p. 2493-2523. In B. N. Fields, D. M. Knipe, and P. M.Howley (ed.), Fields Virology, 3rd ed. Lippincott-Raven Publishers,Philadelphia, Pa.). Primary infection with HCMV is usuallyasymptornatic, although heterophile negative mononucleosis has beenobserved. The virus is horizontally transmitted by sexual contact,breast milk, and saliva. Intrauterine transmission of HCMV from thepregnant mother to the fetus occurs and is often the cause of seriousclinical consequences. HCMV remains in a latent state within theinfected person for the remainder of his/her life. Cell-mediatedimmunity plays a central role in controlling reactivation from latency.Impaired cellular immunity leads to reactivation of latent HCMV inseropositive persons.

[0004] HCMV disease is associated with deficient or immature cellularimmunity. There are 3 major categories of persons with HCMV disease(reviewed by Britt and Alford, 1996). (1) In immunocompromised (AIDS)patients, HCMV is one of the two most common pathogens causing clinicaldisease (the other is Pneumocystis). The most common manifestation ofHCMV in AIDS is retinitis, although infection of other organs includingthe adrenal glands, lungs, GI tract, and central nervous system are alsoreported frequently. 90% of AIDs patients have active HCMV infection;25-40% (85,000 patients in the United States) have life- orsight-threatening HCMV disease. HCMV is the cause of death in 10% ofpersons with AIDs. (2) Due to immune system suppression to reduce therisk of graft rejection, HCMV reactivation or reinfection is commonamongst kidney, liver, heart, and allogeneic bone marrow transplantpatients. Pneumonia is the most common HCMV disease in these patients,occurring in up to 70% of these transplant patients. (3) Congenitalinfection due to HCMV occurs in 1% of all births, about 40K per year. Upto 25% of these infants are symptomatic for HCMV disease between ages0-3 years. HCMV disease is progressive, causing mental retardation andneurological abnormalities, in children. Recent studies suggest thattreatment with anti-HCMV drugs may reduce morbidity in these children.

[0005] Several antiviral drugs are currently being marketed (Bron, D.,R. Snoeck, and L. Lagneaux. 1996. New insights into the pathogenesis andtreatment of cytomegalovirus. Exp. Opin. Invest. Drugs 5:337-344;Crumpacker, C. 1996. Ganciclovir. New Eng. J. Med. 335:721-729; Sachs,S., and F. Alrabiah. 1996. Novel herpes treatments: a review. Exp. Opin.Invest. Drugs 5:169-183). These include: ganciclovir (Roche), anucleoside analog with hemopoietic cell toxicity; foscarnet (Astra), apyrophosphate analog with nephrotoxicity; and cidofovir, Gilead), anucleoside phosphonate with acute nephrotoxicity. Each of these drugstarget the viral-encoded DNA polymerase, are typically administeredintravenously due to their low bioavailability, and, as noted above, arethe source of significant toxicity. Ganciclovir-resistant mutants whicharise clinically are often cross-resistant with cidofovir. Hence, thereis a need for safer (i.e. less toxic), orally bioavailable anti-viraldrugs which are directed against novel viral targets.

[0006] Phenyl thioureas are disclosed for. use in a variety ofpharmaceutical applications. Armistead, et al., WO 97/40028, teachesphenyl ureas and thioureas as inhibitors of the inosine monophosphatedehydrogenase (IMPDH) enzyme which is taught to play a role in viralreplication diseases such herpes.

[0007] Widdowson, et al., WO 96/25157, teaches phenyl urea and thioureacompounds of the below formula for treating diseases mediated by thechemokine, interleukin-8.

[0008] Morin, Jr., et al., U.S. Pat. No. 5,593,993 teaches certainphenyl thiourea compounds for treatment of AIDs and the inhibition ofthe replication of HIV and related viruses.

[0009] Therefore, it is an object of this invention to providecompounds, and pharmaceutically acceptable salts thereof, to inhibitand/or treat diseases associated with herpes viruses including humancytomegalovirus, herpes simplex viruses, Epstein-Barr virus,varicella-zoster virus, human herpesviruses-6 and -7, and Kaposiherpesvirus.

DESCRIPTION OF THE INVENTION

[0010] In accordance with the present invention are provided compoundshaving the formula:

[0011] R₁-R₅ are independently selected from hydrogen, alkyl of 1 to 6carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbonatoms, perhaloalkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbonatoms, heterocycloalkyl of 3 to 10 carbon members, aryl, heteroaryl,halogen, —CN, —NO₂, —CO₂R₆, —COR₆, —OR₆, —SR₆, —SOR₆, —SO₂R₆, —CONR₇R₈,—NR₆N(R₇R8), —N(R₇R8) or W—Y—(CH₂)_(n)—Z; or R₂ and R₃ or R₃ and R₄,taken together form a 3 to 7 membered heterocycloalkyl or 3 to 7membered heteroaryl;

[0012] R₆ and R₇ are independently hydrogen, alkyl of 1 to 6 carbonatoms, perhaloalkyl of 1 to 6 carbon atoms, or aryl;

[0013] R8 is hydrogen, alkyl of 1 to 6 carbon atoms, perhaloalkyl of 1to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, heterocycloalkylof 3 to 10 members, aryl or heteroaryl, or

[0014] R₇ and R₈, taken together may form a 3 to 7 memberedheterocycloalkyl;

[0015] A is heteroaryl;

[0016] W is O, NR₆, or is absent;

[0017] Y is —(CO)— or —(CO₂)—, or is absent;

[0018] Z is alkyl of 1 to 4 carbon atoms, —CN, —CO₂R₆, COR₆, —CO₆NR₇R₈,—OCOR₆, —NR₆COR₇, —OCONR₆, —OR₆, —SR₆, —SOR₆, —SO₂R₆, SR6N(R7R8),—N(R₇R₈) or phenyl;

[0019] G is aryl or heteroaryl;

[0020] X is a bond, —NH, alkyl of 1 to 6 carbon atoms, alkenyl of 1 to 6carbon atoms, alkoxy of 1 to 6 carbon atoms, thioalkyl of 1 to 6 carbonatoms, alkylamino of 1 to 6 carbon atoms, or (CH)J;

[0021] J is alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 7 carbonatoms, phenyl or benzyl; and

[0022] n is an integer from 1 to 6; or a pharmaceutical salt thereof.

[0023] In some preferred embodiments of the present invention at leastone of R₁-R₅ is not hydrogen, and preferably one to three of R₁-R₅ isnot hydrogen. Preferably, R₁-R₅ is selected from hydrogen, alkoxy of 1to 6 carbon atoms, perhaloalkyl of 1 to 6 carbon atoms, and halogen.

[0024] Preferably X is (CH)J where J is alkyl of 1 to 6 carbon atoms.More preferably, J is an alkyl of 1 to 3 carbon atoms and mostpreferably J is methyl.

[0025] A is most preferably unsubstituted.

[0026] In some embodiments of the present invention A may be substitutedwith at least one of hydrogen, alkyl of 1 to 4 carbon atoms,perhaloalkyl of 1 to 4 carbon atoms, halogen, alkoxy of 1 to 4 carbonatoms, or cyano.

[0027] G is preferably a 5 or 6 membered heteroaryl having 1 or 2heteroatoms. More preferably, G is oxazoly, furyl, thiazolyl orthiadiazolyl and in more preferred embodiments, G is 1,2,3 thiadiazolyl,1,3 thiazolyl, or 2-furyl. G is most preferably thiazolyl, and inparticular 1,3 thiazoly.

[0028] Preferred compounds of the present invention are the followingcompounds which include pharmaceutical salts thereof:

[0029] Furan-2-carboxylic acid{5-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-pyridin-2-yl}-amide,

[0030] [1,2,3]Thiadiazole-4-carboxylic acid{5-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-pyridin-2-yl}-amide,

[0031] Pyridine-2-carboxylic acid{5-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-pyridin-2-yl}-amide,

[0032] Pyridine-2-carboxylic acid{6-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-pyridin-3-yl}-amide,

[0033] Furan-2-carboxylic acid{6-[3-5-chloro-2,4-dimethoxy-phenyl)-thioureido]-pyridin-3-yl}-amide,

[0034] [1,2,3]Thiadiazole-4-carboxylic acid{6-[3-5-chloro-2,4-dimethoxy-phenyl)-thioureido]-pyridin-3-yl}-amide,

[0035] [1,2,3]Thiadiazole-4-carboxylic acid{5-[3-(3,5-dichloro-phenyl)-thioureido]-pyridin-2-yl}-amide,

[0036]N-[5-[[[(5-Chloro-2,4-dimethoxyphenyl)amino]thioxomethyl]amino]-2-pyridinyl]-2-methylbenzamide,

[0037]N-(5-[3-{5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-pyridin-2-yl}-2-fluoro-benzamide,

[0038]N-{6-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-pyridin-3-yl}-2-fluoro-benzamide,

[0039]N-{5-[({[3,5-bis(trifluoromethyl)benzyl]amino}carbothioyl)amino]-2-pyridinyl}-1,2,3-thiadiazole-4-carboxamide,

[0040] N-(5-{[({(1S)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}amino)carbothioyl]amino}-2-pyridinyl)-1,2,3-thiadiazole-4-carboxamide,

[0041] N-(5-{[({(IS)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}amino)carbothioyl]amino}-2-pyridinyl)-1,3-thiazole-4-carboxamide,

[0042] N-(5-{[({1 -[2-fluoro-5-(trifluoromethyl)phenyl]ethyl}amino)carbothioyl]amino}-2-pyridinyl)-1,3-thiazole-4-carboxamide,

[0043] N-(5-{[({1 -[2-fluoro-4-(tritluoromethyl)phenyl]ethyl}amino)carbothioyl]amino}-2-pyridinyl)-1,3-thiazole-4-carboxamide,

[0044] N-(5-{[({1-[3-fluoro-5-(trifluoromethyl)phenyl]ethyl}amino)carbothioyl]amino}-2-pyridinyl)-1,3-thiazole-4-carboxamide,

[0045] N-(5-{[({(1S)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}amino)carbonyl]amino}-2-pyridinyl)-1,3-thiazole-4-carboxamide,

[0046]N-{5-[({[1-(3-bromophenyl)ethyl]amino}carbothioyl)amino]-2-pyridinyl}-1,3-thiazole-4-carboxamide,

[0047] N-{5-[{([1-(2-bromophenyl)ethyl]amino}carbothioyl)amino]-2-pyridinyl}-1,3-thiazole-4-carboxamide,

[0048] N-{5-([{(1-[3-(trifluoromethyl)phenyl]ethyl}amino)carbothioyl]amino}-2-pyridinyl)-1,3-thiazole-4-carboxamide,

[0049] N-{5-([{(1-[4-chloro-3-(trifluoromethyl)phenyl]ethyl}amino)carbothioyl]amino}-2-pyridinyl)-1,3-thiazole-4-carboxamide,

[0050]N-{5-[({[1-(4-chloro-3-fluorophenyl)ethyl]amino}carbothioyl)amino]-2-pyridinyl}-1,3-thiazole-4-carboxamide,

[0051] N-{5-[({[1-(4-chloro-2-fluorophenyl)ethyl]amino}carbothioyl)amino]-2-pyridinyl}-1,3-thiazole-4-carboxamide,

[0052]N-{6-[({[1-(4-fluorophenyl)ethyl]amino}carbothioyl)amino]-3-pyridinyl}-1,2,3-thiadiazole-4-carboxamide,

[0053] N-(6-{[({(1S)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}amino)carbothioyl]amino}-3-pyridinyl)-1,2,3-thiadiazole-4-carboxamide; andpharmaceutical salts thereof.

[0054] Alkyl as used herein refers to straight or branched chain loweralkyl of 1 to 6 carbon atoms. Exemplary alkyl groups include methyl,ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl and hexyl.

[0055] Alkenyl as used herein refers to straight or branched chain loweralkyl of 2 to 6 carbon atoms containing at least one carbon-carbondouble bond. Alkenyl includes vinyl groups.

[0056] Alkynyl as used herein refers to straight or branched chain loweralkyl of 2 to 6 carbon atoms containing at least one carbon-carbontriple bond.

[0057] Alkyl, alkenyl and alkynyl groups of the present invention may besubstituted or unsubstituted.

[0058] Cycloalkyl refers to a saturated mono or bicyclic ring system of3 to 10 carbon atoms. Exemplary cycloalkyl groups include cyclopentyl,cyclohexyl and cycloheptyl. Cycloalkyl groups of the present inventionmay be substituted or unsubstituted.

[0059] Heterocycloalkyl refers to a saturated mono or bicyclic ringsystem of 3 to 10 members having 1 to 3 heteroatoms selected from N, Sand O, including, but not limited to aziridinyl, azetidinyl,imidazolidinyl, morpholinyl, thiomorpholinyl, piperazinyl,pyrazolidinyl, piperidinyl, and pyrrolidinyl. Heterocycloalkyl groups ofthe present invention may be substituted or unsubstituted.

[0060] Aryl, as used herein refers to an aromatic mono or bicyclic ringof 5 to 10 carbon atoms. Exemplary aryl groups include phenyl, naphthyl,and biphenyl. Aryl groups of the present invention may be substituted orunsubstituted.

[0061] Heteroaryl as used herein refers to an aromatic mono or bicyclicring of 5 to 10 members having 1 to 3 heteroatoms selected from N, S orO including, but not limited to thiazolyl, thiadiazolyl, oxazolyl,furyl, indolyl, benzothiazolyl, benzotriazolyl, benzodioxyl, indazolyl,and benzofuryl. Preferred heteroaryls include quinolyl, isoquinolyl,napthalenyl, benzofuranyl, benzothienyl, indolyl, pyridyl, pyrazinyl,thienyl; furyl; pyrrolyl, isoxazolyl, oxazolyl, isothiazolyl; thiazolyl,pyrazolyl triazolyl, thiadiazolyl, and imidazolyl. Heteroaryl groups ofthe present invention may be substituted or unsubstituted.

[0062] Perhaloalkyl refers to an alkyl group of 1 to 6 carbon atoms inwhich three or more hydrogens are substituted with halogen.

[0063] Phenyl as used herein refers to a 6 membered aromatic ring.

[0064] Halogen, as used herein refers to chlorine, bromine, iodine andfluorine.

[0065] Unless otherwise limited substitutents are unsubstituted mayinclude alkyl of 1 to 6 carbon atoms, cycloalkyl of 1 to 6 carbon atoms,heterocycloalkyl of Ito, 6 members, perhaloalkyl of 1 to 6 carbon atoms,alkylamino, dialkylamino, aryl or heteroaryl.

[0066] Carbon number refers to the number of carbons in the carbonbackbone and does not include carbon atoms occurring in substituentssuch as an alkyl or alkoxy substituents.

[0067] Where terms are used in combination, the definition for eachindividual part of the combination applies unless defined otherwise. Forinstance, alkylcycloalkyl is an alkyl-cycloalkyl group in which alkyland cycloalkyl are as previously described.

[0068] Pharmaceutically acceptable salts are the acid addition saltswhich can be formed from a compound of the above general formula and apharmaceutically acceptable acid such as phosphoric, sulfuric,hydrochloric, hydrobromic, citric, maleic, succinic, fumaric, acetic,lactic, nitric, sulfonic, p-toluene sulfonic, methane sulfonic acid, andthe like.

[0069] The compounds of this invention contain a chiral center,providing for various seteroisomeric forms of the compounds such asracemic mixtures as well as the individual optical isomers. In somepreferred embodiments of the present invention the compounds of thepresent invention are substantially pure optical isomers. Bysubstantially pure is meant the composition contains greater than 75% ofthe desired isomer and may include no more than 25% of the undesiredisomer. In more preferred embodiments the pure optical isomer is greaterthan 90% of the desired isomer. In some preferred embodiments, when thetarget is VZV, the (S) isomer is preferred. The individual isomers canbe prepared directly or by asymmetric or stereospecific synthesis or byconventional separation of optical isomers from the racemic mixture.

[0070] Compounds of the present invention may be prepared by thoseskilled in the art of organic synthesis employing methods describedbelow which utilize readily available reagents and starting materialsunless otherwise described. Compounds of the present invention are thusprepared in accordance with the following schemes.

[0071] The novel compounds of the present invention are preparedaccording to the following reaction schemes.

[0072] Referring to Methods 31 (reacting 2 and 3, top) and 34 (reacting4 and 5, bottom), reacting appropriately substituted amines 2, whereinthe substitutents R₁-R₅, and X are described as above, withappropriately substituted isothiocyanates 3, wherein A and G aredescribed above, either neat or in an appropriate solvent such astetrahydrofuran, acetonitrile, ethyl acetate, dichloro-methane, orN,N-dimethylformamide affords the desired thioureas 1. Similarly,reaction of appropriately substituted isothiocyanates 4, wherein thesubstitutents R₁-R₅, and X are described as above with appropriatelysubstituted amine 5, wherein A and G are described above, in aconvenient solvent such as those listed above affords the desiredthioureas 1.

Methods 31 and 34

[0073]

[0074] Alternatively, appropriately substituted thioureas 1 can beprepared as described by Methods 32 and 33 by reacting amines 2 and 5,wherein R₁-R5, A and G are described as above, in the presence of eitherone molar equivalent of 1,1′-thiocarbonyl-diimidazole in an appropriatesolvent such as dichloromethane and tetrahydrofuran or mixtures thereofor one molar equivalent of 1,1′-thiocarbonyl-di-(1,2,4)-triazole in anappropriate solvent such as dichloromethane and tetrahydrofuran ormixtures thereof at room temperature.

[0075] In certain instances, subsequent chemical modification of thefinal thioureas 1 was required. These methods, Methods 35-39, aresummarized below.

[0076] Thioureas 1 wherein at least one substituent of R₁-R₅ is1-hydroxyethoxy or carboxy-methoxy, A and G are defined as above and Xequals a bond, may be prepared from the corresponding alkyl esters byalkaline hydrolysis with aqueous sodium or potassium hydroxide in asuitable solvent such as methanol, tetrahydrofuran or mixtures thereofat room temperature in accordance with Methods 35 and 36.

[0077] Thioureas 1 wherein at least one substituent of R₁-R₅ is1-acyloxyethoxy or methansulfonoxyethoxy, A and G are defined as aboveand X equals a bond, may be prepared from the corresponding1-hydroxyethoxy derivative by acylation with appropriate acylatingagents such as benzoic acid chloride or methanesulfonic acid chloride inthe presence of a suitable tertiary amine base such as triethylamine ordiisopropylethylamine in a suitable solvent such as dichloromethane orthe like at room temperature in accordance with Methods 37 and 38.

[0078] Thioureas 1 wherein at least one substituent of R₁-R5 is1-amninoethoxy, A and G are defined as above and X equals a bond, may beprepared from the corresponding 1-methanesulfonoxy-ethoxy derivative byreaction with an appropriate secondary amine such as dimethylamine in asuitable solvent mixture such as tetrahydrofuran and water or the likeat room temperature in accordance with Method 39.

[0079] Thioureas 1 wherein at least one substituent of R₁-R₅ is1-aminoalkyl, A and G are defined as above and X equals a bond, may beprepared from the corresponding 1-azidoalkyl derivative by reaction withstannous chloride in a suitable solvent such as methanol, ethanol or thelike at room temperature in accordance with Method 40.

[0080] The intermediate isothiocyanates 3 and 4 shown above in Methods31 and 34 are prepared in accordance with Method 41 (below) essentiallyaccording to the procedures of Staab, H. A. and Walther, G. JustusLiebigs Ann. Chem. 657, 104 (1962)) by reacting appropriatelysubstituted amines 5 or 2, respectively, wherein R₁-R₅, A and G aredescribed above and X equals a bond, with one molar equivalent of1,1′-thiocarbonyldiimidazolein an appropriate solvent such asdichloromethane and tetrahydrofuran or mixtures thereof.

Method 41

[0081]

[0082] The intermediates 2 and 5 may be prepared according to thefollowing protocols:

[0083] According to Methods 1A-1G, amines 2, wherein R₁-R₅ and X aredefined above and amines 5, wherein A is defined above, may be preparedby reduction of the appropriately substituted nitrobenzenes according toa variety of procedures known to those skilled in the art and describedin R. J. Lindsay, Comprehensive Organic Chemistry (ed. Sutherland),Volume 2, Chapter 6.3.1, Aromatic Amines, 1979. Such procedures includethe reduction of nitrobenzenes to form anilines upon exposure to:

[0084] a) iron powder and a strong acid, such as hydrochloric acid(Methods 1A) either neat or in alcohol solvent such as methanol orethanol, at temperatures ranging from room temperature to the refluxingtemperature of the solvent, or;

[0085] b) iron powder and glacial acetic acid (Method 1B), either neator in alcohol solvent such as methanol or ethanol, at temperaturesranging from room temperature to the refluxing temperature of, thesolvent, or;

[0086] c) iron powder and aqueous ammonium chloride (Method 1C), eitherneat or in alcohol solvent such as methanol or ethanol, at temperaturesranging from room temperature to the refluxing temperature of thesolvent, or;

[0087] d) tin and a strong mineral acid, such as hydrochloric acid(Method 1D), either neat or in alcohol solvent such as methanol orethanol, at temperatures ranging from room temperature to the refluxingtemperature of the solvent, or;

[0088] e) when R₁-R₅ and substituents of A are selected from Cl, Br, I,—(OSO₂)—CF₃, or —(OSO₂)-1-(4-methylphenyl), by catalytic reduction suchas with hydrogen and palladium on carbon (Method 1E) in an appropriatesolvent such as methanol, ethanol, or ethyl acetate, under one or moreatmospheres of pressure or;

[0089] f) when R₁-R₅ and R₉-R₁₂ are selected from Cl, Br, I, —(OSO)—CF₃,or —(OSO₂)-1-(4-methylphenyl), by catalytic reduction such as withcyclohexene and palladium on carbon (Method 1F) in an appropriatesolvent such as methanol or ethanol, at temperatures ranging from roomtemperature to the refluxing temperature of the solvent, or;

[0090] g) aqueous sodium hydrosulfite in alcohol solvent at temperaturesranging from room temperature to the refluxing temperature of thesolvent (Method IG).

[0091] Alternatively, according to Methods 3A-3C, amines 2, whereinR₁-R₅ are defined above and X is defined as above and anilines 5,wherein A is defined above, may be prepared by the cleavage of theaniline nitrogen-carbon bond of amide and carbamate derivatives of theseanilines according to a variety of procedures known to those skilled inthe art and described in Greene, Protective Groups in Organic Synthesisvolume 2, Chapter 7, 1991, and references therein. Such proceduresinclude:

[0092] a) the exposure of appropriately substitutedarylamino-tert-butyl-carbamates to a strong acid such as trifluoroaceticacid (Method 3A)either neat or in an appropriate solvent such asdichloromethane at temperatures between 0° C. and room temperature, or;

[0093] b) the exposure of appropriately substitutedarylamino-(2-trimethylsilylethyl)-carbamates to a fluoride ion sourcesuch as tetrabutylammonium fluoride or potassium fluoride (Method 3B) inaqueous acetonitrile or tetrahydrofuran or mixtures thereof attemperatures ranging from room temperature to the reflux temperature ofthe solvent, or;

[0094] c) the exposure of appropriately substitutedarylamino-trifluoroacetamides to a strong base such as sodium orpotassium hydroxide or sodium or potassium carbonate in an alcoholsolvent such as methanol or ethanol (Method 3C) at temperatures rangingfrom room temperature to the reflux temperature of the solvent.

[0095] Alternatively, according to Method 11, amines 2, wherein R₁-R₅are defined above, and X equals a bond and at least one substituent ofR₁-R₅ is defined as vinyl, may be prepared by the palladium catalyzedcoupling of a vinyl trialkyltin reagent, such as tributylvinyltin, withan appropriately substituted bromo- or iodo-aniline, for example3-chloro-4-iodo-aniline, employing a palladium catalyst, such astris(dibenzylidineacetone)-bipalladium, and a ligand, such astriphenylarsine, in a suitable solvent such as tetrahydrofuran orN-methylpyrrolidinone, at temperatures ranging from room temperature tothe reflux temperature of the solvent, essentially according to theprocedures of V. Farina and G. P. Roth in Advances in Metal-OrganicChemistry, Vol. 5, 1-53, 1996 and references therein.

[0096] Alternatively, according to Method 42, amines 2, wherein R₁-R₅are defined above and X is defined as above and at least one substituentof R₂ or R₄ is defined as dialkyiamino, may be prepared by the palladiumcatalyzed amination of an appropriately substituted 3- or 5-bromo- oriodo-aniline, for example 3-amino-5-bromobenzotrifluoride, by secondaryamines under conditions which employ a palladium catalyst, such asbis(dibenzylidineacetone)palladium, and a ligand, such astri-o-tolylphosphine, and at least two molar equivalents of a strongbase, such as lithium bis-(trimethylsilyl)amide in a sealed tube, in asuitable solvent such as tetrahydrofuran or toluene, at temperaturesranging from room temperature to 100° C., essentially according to theprocedures of J. F. Hartwig and J. Louie Tetrahedron Letters 36 (21),3609 (1995).

[0097] Alternatively, according to Method 43, amines 2, wherein R₁-R₅are defined above and X is defined as above and at least one substituentof R₂ or R₄ is defined as alkyl, may be prepared by the palladiumcatalyzed alkylation of an appropriately substituted 3- or 5-bromo-oriodo-aniline, for example 3-amino-5-bromobenzotrifluoride by alkenesunder condiditons which employ a palladium catalyst such as[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)chloride-dichloromethane complex and in the presence of9-borabicyclo[3.3.1]nonane and a suitable base such as aqueous sodiumhydroxide in a suitable solvent such as tetrahydrofuran or the like attemperatures ranging from room temperature to the reflux temperature ofthe solvent.

[0098] The acyl and carbamoyl amine derivatives utilized as startingmaterials in Methods 3A-3C may be prepared by the derivatization of thecorresponding amines as described in Methods 2A-2G according to avariety of procedures known to those skilled in the art and described inGreene, Protective Groups in Organic Synthesis volume 2, Chapter 7,1991, and references therein. Such procedures include:

[0099] a) the reaction of an appropriately substituted amine withdi-tert-butyl-dicarbonate (Method 2A) in the presence or absence of oneor more molar equivalents of a tertiary amine such as triethylamine orN,N-diisopropylethylamine in a suitable solvent such as acetone,tetrahydrofuran, dimethylformamide, dichloromethane, and the like, attemperatures ranging from room temperature to the reflux temperature ofthe solvent to produce the corresponding arylamino-tert-butyl-carbamate,or;

[0100] b) the reaction of an appropriately substituted aniline with1-[2-(trimethylsilyl)ethoxycarbonyl-oxy]benzotriazole (Method 2B) in thepresence of a tertiary amine such as triethylamine ordiisopropylethylamine in a suitable solvent such as dimethylformamide atroom temperature to produce the correspondingarylamino-(2-trimethylsilylethyl)-carbamate, or;

[0101] c) the reaction of an appropriately substituted aniline with acarboxylic acidchloride or acid anhydride (Method 2C) either neat or inan appropriate solvent such as tetrahydrofuran, dimethylformamide,dichloromethane, pyridine and the like, in the presence of one or moremolar equivalents of a teriary amine base such as triethylamine orN,N-diisopropylethyl-amine to produce the corresponding arylaminoamide,or;

[0102] d) the reaction of an appropriately substituted nitro anilinewith a carboxylic acid chloride (Method 2D) in the absence of one ormore molar equivalents of a teriary amine base such as triethylamine orN,N-diisopropylethylamine either neat or in an appropriate solvent suchas tetrahydrofuran, 1,4-dioxane and the like at temperatures rangingfrom room temperature to the reflux temperature of the solvent toproduce the corresponding nitro arylaminoamide, or;

[0103] e) the reaction of an appropriately substituted aniline with acarboxylic acid (Method 2E) in the presence of a coupling agent such asbenzotriazole-1-yloxy-tris-(dimethylamino)-phosphoniumhexafluorophosphate,2-(1H-benzotriazole-1-yloxy)-1,1,3,3-tetra-methyluroniumhexafluorophosphate, dicyclohexyl carbodiimide and the like and in thepresence of a tertiary amine such as triethylamine ordiisopropylethylamine in a suitable solvent such as diichloromethane,dimethylformamide and the like, at room temperature to produce thecorresponding arylaminoamide, or;

[0104] f) the reaction of an appropriately protected aniline such as anarylamino-tert-butyl-carbamate or the like in which at least onesubstituent of R5 and substituents of A are defined as —W—Y—(CK₂)_(n)—Zwherein W, Y, and Z are defined as above, with a carboxylic acidanhydride (Method 2F) in the presence of a suitable base such aspyridine in an appropriate such as dichloromethane, dimethylformamide orthe like at temperatures ranging from 0° C. to room temperature toproduce the corresponding carboxylic acid ester, or;

[0105] g) the reaction of an appropriately substituted aniline in whicha t least one substituent of R₁-R5 is defined as hydroxyl withdi-tert-butyl-dicarbonate (Method 2G) in the absence of one or moremolar equivalents of a tertiary amine such as triethylamine orN,N-diisopropylethylamine in a suitable solvent such as acetone,tetrahydrofuran, dimethylformamide, dichloromethane, and the like, attemperatures ranging from room temperature to the reflux temperature ofthe solvent to produce the corresponding arylamino-tert-butyl-carbamate.

[0106] Nitrobenzene intermediates that are ultimately converted toamines 2 and 5 by methods shown above in Methods 1A-1G may be preparedin accordance with Methods 4A, 4C, 4E-4F.

[0107] Referring to Methods 4A, 4C, and 4E-4H, the nitrobenzeneintermediates which are ultimately converted into amines 2, R, and R₄are defined above and R₁, R₃, and/or R₅ are defined as alkoxy,thioalkoxy, alkylsulfenyl, alkylsulfinyl, and dialkylamino may beprepared by the nucleophilic displacement of appropriately substituted2-, 4-, and/or 6-fluoro-, chloro-, bromo-, iodo-,trifluoromethylsulfonyl-, or (4-methylphenyl)sulfonyl-substitutednitrobenzenes by methods which include the following:

[0108] a) reaction of alcohols with appropriately substituted 2- or 4-halo- or sulfonate esters of nitrobenzenes or benzonitriles (Method 4A)either neat or in an appropriate solvent such as tetrahydrofuran,dioxane, acetonitrile, N,N-dimethylformamide or dimethylsulfoxide in thepresence or absence of one or more molar equivalents of a base such assodium carbonate, potassium carbonate, sodium hydroxide, potassiumhydroxide, sodium hydride, potassium hydride, or the like, attemperatures ranging from room temperature to the reflux temperature ofthe solvent;

[0109] b) reactions of preformed sodium, lithium, or potassiumphenoxides with appropriately substituted 2- or 4- halo- or sulfonateesters of nitrobenzenes or benzonitriles (Method 4H) either neat or inan appropriate solvent such as tetrahydrofuran, dioxane, acetonitrile,N,N-dimethylformamide or dimethylsulfoxide, at temperatures ranging fromroom temperature to the reflux temperature of the solvent, or;

[0110] c) reaction of ammonia, primary or secondary amines withappropriately substituted 2- or 4-halo- or sulfonate esters ofnitrobenzenes or benzonitriles (Methods 4C,F) either neat or in anappropriate solvent such as tetrahydrofuran, dioxane, acetonitrile,N,N-dimethyl-formamide or dimethylsulfoxide, at temperatures rangingfrom room temperature to the reflux temperature of the solvent;

[0111] d) reaction of preformed sodium, lithium, or potassium salts ofamines with appropriately substituted 2- or 4- halo- or sulfonate estersof nitrobenzenes or benzonitriles (Method 4G) in an appropriate solventsuch as tetrahydrofuran at temperatures ranging from 0° C. to the refluxtemperature of the solvent, or;

[0112] e) reaction of sodium sulfide with appropriately substituted 2-or 4- halo- or sulfonate esters of nitrobenzenes or benzonitriles eitherneat or in an appropriate solvent such as tetrahydro-furan, dioxane,acetonitrile, N,N-dimethylformamide or dimethylsulfoxide, attemperatures ranging from room temperature to the reflux temperature ofthe solvent, followed by the addition of an alkyl halide directly to thereaction mixture (Method 4E).

[0113] Alternatively, referring to Methods SC and 6, the nitrobenzeneintermediates which are ultimately converted into amines 2, wherein atleast one substitutent R₁-R₅ is defined as alkoxy may be prepared fromthe corresponding substituted hydroxy-nitrobenzenes by methods whichinclude the following:

[0114] a) reaction of the hydroxy-nitrobenzene with an alkyl halide ordialkyl sulfonate ester (Method 5C) in the presence of a base, such aspotassium carbonate, sodium carbonate, potassium hydroxide, sodiumhydroxide, potassium hydride, or sodium hydride, in an appropriatesolvent such as acetone, N,N-dimethylformamide, tetrahydrofuran ordimethylsulfoxide at temperatures ranging from room temperature to thereflux temperature of the solvent, or;

[0115] b) reaction of the hydroxy-nitrobenzene with an alkyl alcohol,triphenylphosphine, and a dialkylazadicarboxylate reagent (Method 6),such as diethylazodicarboxylate, in an anhydrous aprotic solvent such asdiethyl ether or tetrahydrofuran at temperatures ranging from 0° C. tothe reflux temperature of the solvent, essentially according to methodsdescribed in Mitsunobu, O, Synthesis 1981, 1 and references therein.

[0116] In addition, referring to Method 5A and 5E, the carbamoyl aminederivatives utilized as starting materials in Methods 3A-3C which areultimately converted into amines 2, wherein at least one substituentRL-R₅ is defined as alkoxy may be prepared the corresponding substitutedhydroxy arylamino-tert-butyl-carbamate by reaction with alkyl halides,trifluormethane-sulfonates, 4-methylbenzenesulfonates, dialkylsulfonate,ethylene carbonate and the like in the presence of a suitable base suchas potassium carbonate in an appropriate solvent such as acetone,toluene, or N,N-dimethyl-formamide at temperatures ranging from roomtemperature to the reflux temperature of the solvent.

[0117] Alternatively, referring to Methods 7A-G, the nitrobenzeneintermediates which are ultimately converted into amines 2, R₁ and/or R₃is alkoxy, and R₂ and/or R₄ is a halogen, and X equals a bond, may beprepared by standard halogenation reactions which include the following:

[0118] a) reaction of a 2- or 4- hydroxy-nitrobenzene with aqueoussodium hypochlorite (Methods 7A and 7B), at room temperature or;

[0119] b) reaction of a 2-hydroxy-4-methoxy or 2,4-dimethoxynitrobenzene(Method 7C and 7D) with bromine in suitable solvent such as chloroform,dichlormethane, glacial acetic acid or the like in the presence or theabsence of silver trifluoroacetate at room temperature, or;

[0120] c) reaction of a 2,4-dimethoxynitrobenzene (Method 7E) withbenzyltrimethylammonium dichloroiodate in the presence of anhydrous zincchloride in a suitable solvent such as glacial acetic acid, at roomtemperature or;

[0121] d) reaction of a 2-hydroxy-4-methoxynitrobenzene (Method 7F) withbenzyltrimethyl-ammonium dichloroiodate in the presence of sodiumbicarbonate in a suitable solvent mixture such as dichloromethane andmethanol, at room temperature or;

[0122] d) reaction of a 2,4-dimethoxynitrobenzene (Method 7G) with3,5-dichloro-1-fluoropyridine triflate in a suitable solvent such astetrachloroethane, at a temperature ranging from room temperature to thereflux temperature of the solvent.

[0123] Referring to Method 8, the nitrobenzene intermediates which areultimately converted into amines 2, wherein R₄═—CF₃, and R₁-R₃ and R₅-R₈are defined as above and X equals a bond may be prepared from thecorresponding substituted 4-iodo-nitrobenzenes by reaction withtrimethyl(trifluoromethyl)silane in the presence of cuprous iodide andpotassium fluoride in a suitable solvent such as N,N-dimethyl-formamideor the like at a temperature ranging from room temperature to the refluxtemperature of the solvent in a sealed reaction vessel.

[0124] Referring to Methods 19A and 19B, the nitrobenzene intermediateswhich are ultimately converted into amines 2, wherein R₄═—HNCOCH₂NR₇R₈or —HNCOCH₂SR₆, and R₁-R₃ and R₅-R₈ are defined as above and X equals abond may be prepared from the corresponding substituted4-(N-chloroacetyl)-nitroaniline by reaction with either a suitablesecondary amine such as dimethylamine, morpholine or the like in asuitable solvent such as tetrahydrofuran and/or water mixtures attemperatures ranging from room temperature to the reflux temperature ofthe solvent or by reaction with an appropriate thiol in the presence ofa suitable base such as sodium or potassium carbonate or the like in asuitable solvent such as tetrahydrofuran, 1,4-dioxane or the like attemperatures ranging from room temperature to the reflux temperature ofthe solvent.

[0125] Referring to Method 25, the nitrobenzene intermediates which areultimately converted into amines 2, wherein at least one substituent ofR₁-R₅ is defined as triflate and X equals a bond may be prepared fromthe corresponding phenol by reaction with trifluoromethane-sulfonicanhydride in the presence of a tertiary amines such as triethylamine ordiisopropyl-ethylamine or the like in a suitable solvent such asdichloromethane at temperatures ranging from 0° C. to room temperature.

[0126] Referring to Methods 9, 9B, and 10, the carbamoyl aminederivatives utilized as starting materials in Methods 3A-3C which areultimately converted into amines 2, wherein at least one substituentR₁-R₅ is defined as either alkylsulfenyl or alkylsulfinyl, may beprepared by reaction of the appropriate 4-alkylthio acyl-arylamino orcarbamoyl arylamino derivative with an appropriate oxidizing agent suchas dimethyloxirane or sodium periodate in a suitable solvent mixturesuch as acetone and dichloromethane or water at room temperature.

[0127] Referring to Method 12, the carbamoyl amine derivatives utilizedas starting materials in Methods 3A-3C which are ultimately convertedinto amines 2, wherein R₄ is defined as 1-hydroxyethyl and R₁-R₃ and R5are defined as above and X equals a bond may be prepared by reacting thecorresponding 4vinyl carbamoyl aniline with sodium borohydride in thepresence of mercuric acetate in a suitable solvent such astetrahydrofuran, 1,4-dioxane or the like and water at room temperature.

[0128] Referring to Method 13, the carbamoyl amine derivatives utilizedas starting materials in Methods 3A-3C which are ultimately convertedinto amines 21, wherein R₄ is defined as 2-hydroxyethyl and R₁-R₃ and R₅are defined as above and X equals a bond, may be prepared by reactingthe corresponding 4-vinyl carbamoyl aniline with sodium borohydride inthe presence of glacial acetic acid in a suitable solvent such astetrahydrofuran, 1,4-dioxane or the like at temperatures ranging from 0°C. to room temperature.

[0129] Referring to Method 14, the carbamoyl amine derivatives utilizedas starting materials in Methods 3A-3C which are ultimately convertedinto amines 2, wherein R₄ is defined as 1-azidoethyl and R₁R₃ and R₅ aredefined as above and X is defined as above, may be prepared by reactingthe corresponding 4-(1-hydroxyethyl) carbamoyl aniline with hydrazoicacid in the presence of a dialkylazodicarboxylate such asdiethylazodicarboxylate and triphenylphosphine in a suitable solventmixture such as tetrahydrofuran and dichloromethane at temperaturesranging from 0° C. to room temperature.

[0130] Referring to Method 15, the carbamoyl amine derivatives utilizedas starting materials in Methods 3A-3C which are ultimately convertedinto amines 2, wherein R₄ is defined as 3-dimethylaminoprop-1-ynyl andR₁-R₃ and R₅ are defined as above and X is defined as above, may beprepared by reacting the corresponding 4-iodocarbamoyl aniline withl-dimethylamino-2-propyne in a suitable tertiary amine solvent such astriethylamine or diisopropylethylamine in the presence ofbis(triphenylphosphine)palladium(II) chloride and cuprous iodide attemperatures ranging from room temperature to the reflux temperature ofthe solvent.

[0131] Referring to Method 16, the carbamoyl amine derivatives utilizedas starting materials in Methods 3A-3C which are ultimately convertedinto amines 2, wherein R₄ is defined as 3-dimethylaminoacryloyl andR₁-R₃ and R₅ are defined as above and X equals a bond, may be preparedby reacting the corresponding 4-(3-dimethylaminoprop-1-ynyl)carbamoylaniline with a suitable peracid such as 3-chloroperoxybenzoic acid in asuitable solvent mixture such as dichloromethane and methanol attemperatures ranging from 0° C. to room temperature.

[0132] Referring to Methods 17 and 18, the carbamoyl amine derivativesutilized as starting materials in Methods 3A-3C which are ultimatelyconverted into amines 2, wherein R₄ is defined as either 4-isoxazol-5-ylor 4-(1H-pyrazol-3-yl) and R₁-R₃ and R₅ are defined as above and Xequals a bond, may be prepared by reacting the corresponding4-(3-dimethylamino-acryloyl)carbamoyl aniline with either hydroxylaminehydrochloride or hydrazine hydrate in a suitable solvent such as1,4-dioxane or ethanol and the like at room temperature.

[0133] Referring to Method 20, the carbamoyl amine derivatives utilizedas starting materials in Methods 3A-3C which are ultimately convertedinto amines 2, wherein R₄═—HNCO₂Z, and R₁-R₃, R₅, and Z are defined asabove and X equals a bond, may be prepared by reacting the corresponding4-aminocarbamoyl aniline with 1,1-carbonyl-di-(1,2,4)-triazole and anappropriately substituted alcohol in a suitable solvent mixture such astetrahydrofuran and dichloromethane and the like at temperatures rangingfrom room temperature to the reflux temperature of the solvent.

[0134] Referring to Methods 26 and 30, the carbamoyl amine derivativesutilized as starting materials in Methods 3A-3C which are ultimatelyconverted into amines 2, wherein at least one substituent of R₁-R₅ isdefined as dialkylamino and X is defined as above, may be prepared byreaction of appropriately substituted aldehydes in the presence ofeither sodium cyanoboro-hydride or hydrogen gas and 10 % palladium oncarbon in a suitable solvent such as water, methanol, tetrahydrofuranmixtures or toluene or the like at room temperature.

[0135] Referring to Methods 27 and 28, amities 2 wherein at least onesubstituent of R₁-R₅ is defined as hydroxy and X is defined as above canbe prepared by reaction of the corresponding ester such as acetate withan appropriate base such as sodium bicarbonate or sodium hydroxide in asuitable solvent mixture such as methanol-water mixtures at temperaturesranging from room temperature to the reflux temperature of the solvent.

[0136] Referring to Method 29, amines 2 wherein at least one substituentof R₁-R₅ is defined as 2-hydroxybenzamido and X is defined as above canbe prepared by reaction of the correspondingN-(4-aminophenyl)phthalimide with lithium borohydride in an appropriatesolvent such as tetrahydrofuran, diethyl ether, or the like at roomtemperature.

[0137] The intermediate amines 2 wherein R₁-R₅ are defined as above andX equals either —CH₂— or —(CH₂)₂— can be prepared by the followingprocedures:

[0138] a) reduction of an appropriately substituted benzo- orphenylacetonitrile with borane-dimethylsulfide complex in a suitablesolvent such as ethylene glycol dimethyl ether, tetrahydrofuran or thelike a temperatures ranging from room temperature to the refluxtemperature of the solvent. (Method 44);

[0139] b) Reduction under one or more atmospheres of hydrogen in thepresence of a suitable catalyst such as 5 % or 10 % palladium on carbonand an acid such as 4-methyl-benzenesulfonic acid, hydrochloric acid orthe like in a suitable solvent such as ethylene glycol monomethyl ether,ethyl acetate, ethanol or the like at room temperature. (Method 50);

[0140] c) reduction with lithium aluminum hydride in a suitable solventsuch as tetrahydrofuran or diethyl ether at temperatures ranging from 0°C. to room temperature. (Method 51);

[0141] The unsaturated nitro precursors which are utilized as startingmaterials in Method 51 and are ultimately converted to amines 2 whereinR₁-R₅ are defined as above and X equals —(CH)₂— can be prepared byreaction of an appropriately substituted benzaldehyde with nitro-methanein the presence of ammonium acetate in a suitable solvent such as aceticacid at temperatures ranging from room temperature to the refluxtemperature of the solvent.(Method 53); The benzaldehydes, utilized asstarting materials in Method 53, can be prepared by diisobutylaluminumhydride reduction of an appropriately substituted benzonitrile. (Method52) The substituted benzonitriles, utilized as starting materials inMethod 52, can be prepared from the corresponding aryl bromide byreaction with copper cyanide in a suitable solvent such asN,N-dimethylformamide at temperatures ranging from room temperatture tothe reflux temperature of the solvent. (Method 59).

[0142] For amines 2, wherein R₁-R₅ is defined as above and X equalseither —O(CH,)₂NH₂ or —S(CH₂)₂NH₂, the requisite nitrile precursors maybe prepared by reaction of an appropriately substituted phenol orthiophenol with bromoacetonitrile in the presence of a suitable basesuch as potassium carbonate in an appropriate solvent such as acetone atroom temperature according to Method 49.

[0143] Alternatively, for amines 2, wherein R₁-R₅ are defined as aboveand X equals —(CH₂)₃—, the nitrile precursors can be preparedessentially according to the procedure of Wilk, B. Synthetic Comm. 23,2481 (1993), by reaction of an appropriately substituted phenethanolwith acetone cyanohydrin and triphenylphosphine in the presence of asuitable azodicarboxylate such as diethyl azodicarboxylate in anappropriate solvent such as diethyl ether or tetrahydro-furan or thelike at temperatures ranging from 0° C. to room temperature. (Method54).

[0144] Alternatively, intermediate amines 2 wherein R₁-R₅ are defined asabove and X equals —(CH(CH₃))— can be prepared by acid or base catalyzedhydrolysis of the corresponding formamide using an appropriate acidcatalyst such as 6N hydrochloric acid or a suitable base catalyst suchas SN sodium or potassium hydroxide in an appropriate solvent mixturesuch as water and methanol or water and ethanol at temperatures rangingfrom room temperature to the reflux temperature of the solvent. (Method46)

[0145] The formamide precursors utilized as starting materials in Method46 and which are ultimately converted into amines 2, are preparedaccording to Method 45 by treatment of an appropriately substitutedacetophenone with ammonium formate, formic acid and formamide attemperatures ranging from room temperature to the reflux temperature ofthe solvent.

[0146] Alternatively, amines 2 wherein R₁-R₅ are defined as above and Xequals —(CH(CH₃))— can be prepared by reduction of an appropriatelysubstituted O-methyl oxime in the presence of sodium borohydride andzirconium tetrachloride in a suitable solvent such as tetrahydrofuran ordiethyl ether at room temperature Method 48 essentially according to theprocedure of Itsuno, S., Sakurai, Y., Ito, K. Synthesis 1988, 995. Therequisite O-methyl oximes can be prepared from the correspondingacetophenone by reaction with methoxylamine hydrochloride and pyridinein a suitable solvent such as ethanol or methanol at temperaturesranging from room temperature to the reflux temperature of the solvent.(Method 47)

[0147] Amines 2 for which R₁-R₅ are defined as above and X equals—CH(J)— where J is defined as above, can be prepared by reduction of theappropriately substituted ketone by the methods described above (Methods45, 47, and 48). These requisite ketones, when not commerciallyavailable, can be prepared by reaction of a suitably substitutedbenzaldehyde with an appropriate organometallic reagent such asphenyllithium, isopropylmagnesium bromide or ethylmagnesium bromide orthe like in a suitable solvent such as diethyl ether or tetrahydrofuranat temperatures ranging from −78° C. to 0° C. (Method 57) The resultingalcohols can be oxidized to the corresponding ketone with an appropriateoxidizing agent such as chromium trioxide in aqueous sulfuric acid andacetone or pyridinium chlorochromate or pyridium dichromate in anappropriate solvent such as dichloromethane or the like at roomtemperature. (Method 58)

[0148] The intermediate anilines 5 may be prepared as previouslydescribed Method 3A. Thus treating phenyl carbamic acid tert-butyl ester6 or the corresponding heteroaryl, wherein X equals a bond and G aredescribed as above, with neat trifluoroacetic acid at room temperaturefollowed by neutralization with aqueous sodium hydroxide affords thedesired anilines 5. The requisite carbamic acid esters 6, wherein A andG are described as above, are prepared as shown in Method 2C by reactionof substituted acid chlorides, 8, where G is described as above, and4-aminophenyl-carbarnic acid tert-butyl esters 7 or the correspondingheteroaryl, wherein A is described above, in the presence oftriethylamine in an appropriate solvent such as dichloromethane,dimethylsulfoxide, or dimethylformamide or mixturestthereof. Carboxylicacid chlorides 8 are either commercially available or prepared from thecorresponding carboxylic acid by reaction with oxalyl chloride in asuitable solvent such as dichloromethane at room temperature.

Method 3A, 2C

[0149]

[0150] Alternatively, amines 5 may be prepared as previously describedby methods IA-IG. Thus, treating 2-amino-5-nitropyridine (7) withheterocyclic acid chlorides 8 or other activated acid derivatives asdescribed in Methods 2C-2E affords the nitro amide 6, where G isdescribed as above. Subsequent reduction by procedures described inMethods 1A-1G affords amines 5.

[0151] Alternatively, carbamic acid esters 6, wherein A and G aredescribed as above, are prepared as shown in Method 2E by reaction ofsubstituted carboxylic acids 8a, wherein G is described as above, and anappropriately substituted 4-aminophenyl carbamic acid tert-butyl esters7 or the corresponding heteroaryl in the presence of a suitable couplingagent such as benzotriazole-1-yloxy-tris-(dimethylamino)-phosphoniumhexafluorophosphate,2-(1H-benzotriazole-1-yloxy)-1,1,3,3-tetra-methyluroniumhexafluorophosphate, dicyclohexyl carbodiimide or the like and in thepresence of a tertiary amine base such as triethylamine ordiisopropylethylamine in a suitable solvent such as dichloromethane,dimethylformamide and the like, at room temperature to produce thecorresponding heteroaryl or arylaminoamide.

[0152] Carboxylic acids 8a are either commercially available or areprepared according to literature methods. For example, when G is asubstituted thiadiazole, the acid is available from the correspondingcarboxylic acid ester by reaction with an appropriate base such assodium or potassium hydroxide in a suitable solvent mixture such asmethanol or ethanol and water at room temperature.

[0153] Similarly, when G is either substituted or unsubstitutedthiazole, substituted or unsubstituted oxazole, substituted orunsubstituted isothiazole or substituted or unsubstituted isoxazole,when not commercially available, the corresponding carboxylic acid 8a isavailable from the corresponding ethyl or methyl ester by reaction withan appropriate base such as sodium or potassium hydroxide in a suitablesolvent mixture such as methanol or ethanol and water at roomtemperature. These esters are either commercially available or can beprepared according to literature methods.

[0154] When the carboxylic acid ester precursors which are ultimatelyconverted to acids 8a are not commmercially available, they may beprepared by methods known in the literature. For example,5-substituted-1,2,3-thiadiazole-4 carboxylic acid esters may be preparedessentially according to the procedure of Caron, M J. Org. Chem. 51,4075 (1986) and Taber, D. F., Ruckle, R. E. J. Amer. Chem. Soc. 108,7686 (1986). Thus, according to Method 21, treatment of a beta-ketocarboxylic acid ester with 4-methylbenzenesulfonyl azide ormethanesulfonyl azide or the like in the presence of a tertiary aminebase such triethylamine or diisopropylethylamine in a suitable solventsuch as acetonitrile affords the corresponding diazo-beta-ketocarboxylic acid ester. Treatment of this compound with2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide in asuitable solvent such as benzene or toluene or the like at temperaturesranging from room temperature to the reflux temperature of the solventgives the desired 5-substituted-1,2,3-thiadiazole-4-carboxylic acidester.

[0155] Alternatively, 4-substituted-1,2,3-thiadiazole -5-carboxylic acidesters may be prepared essentially according to the procedure ofShafiee, A., Lalezari, I., Yazdani, S., Shahbazian, F. M., Partovi, T.J. Pharmaceutical Sci. 65, 304 (1976). Thus, according to Method 22 and23, reaction of an appropriately substituted beta-keto carboxylic acidester in a suitable alcoholic solvent such as methanol or ethanol withan aqueous solution semicarbazide hydrochloride at temperatures rangingfrom room temperature to the reflux temperature of the solvent in thepresence of a suitable base such as pyridine gives correspondingsemicarbazone derivative. Treatment of this compound with neat thionylchloride at 0° C. followed by treatment with an excess aqueous solutionof sodium bicarbonate affords the corresponding4-substituted-1,2,3-thiadiazole-5-carboxylic acid esters.

[0156] 4-carboalkoxythiazoles are prepared essentially according to theprocedure of Schöllkopf, U., Porsch, P., Lau, H. Liebigs Ann. Chem. 1444(1979). Thus, according to Method 55 and 56, reaction of ethylisocyanoacetate with N,N-dimethylformamide dimethyl acetal in a suitablealcoholic solvent such as ethanol at room temperature gives thecorresponding 3-dimethylamino-2-isdcyano-acrylic acid ethyl ester. Asolution of this compound in a suitable solvent such as tetrahydrofuranis treated with gaseous hydrogen sulfide in the presence of a suitabletertiary amine base such as triethylamine or diiso-propylethylamine orthe like at room temperature to give the corresponding4-carboethoxy-thiazole.

[0157] Additional appropriately substituted thiazoles may be preparedessentially according to the procedure of Bredenkamp, M. W., Holzafel,C. W., van Zyl, W. J. Synthetic Comm. 20, 2235 (1990). Appropriateunsaturated oxazoles are prepared essentially according to the procedureof Henneke, K. H., Scholkopf, U., Neudecker, T. Liebigs Ann. Chem. 1979(1979). Substituted oxazoles may be prepared essentially according tothe procedures of Galeotti, N., Montagne, C., Poncet, J., Jouin, P.Tetrahedron Lett. 33, 2807, (1992) and Shin, C., Okumura, K., Ito, A.,Nakamura, Y. Chemistry Lett 1305, (1994).

[0158] The following specific examples are illustrative, but are notmeant to be limiting of the present invention.

EXAMPLE 1 (METHOD 1A) 4-Methoxy-3-trifluoromethyl-phenylamine

[0159] A suspension of 4-methoxy-3-trifluoromethyl-nitrobenzene (2.2 g)and iron powder (1.68 g) in ethanol (35 mL) and water (15 mL) is treatedwith a solution of concentrated hydrochloric acid (0.42 mL) in ethanol(6 mL) and water (3 mL) and the mixture is heated to reflux forapproximately 1 hour. The mixture is then cooled, filtered, andconcentrated under reduced pressure. The resulting oil is dissolved inethyl acetate and extracted three times with 5% aqueous hydrochloricacid. The pooled acidic extracts are then cooled in an ice bath andbasified with solid potassium carbonate, then extracted with ethylacetate. These organic extracts are washed with saturated aqueous sodiumchloride, dried over anhydrous sodium sulfate, concentrated underreduced pressure, then passed through a short column of silica gel(ethyl acetate is used as the eluant) to provide, the desired compoundas an amber oil.

[0160] Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

[0161] 2,6-Dichloro-benzene-1,4-diamine

[0162] 3-Chloro-4-methylsulfanyl-phenylamine

[0163] 2,6-Dibromo-benzene-1,4-diamine

[0164] 3-Chloro-4-trifluoromethyl-phenylamine

[0165] 3-Chloro-4-ethylsulfanyl-phenylamine

[0166] 4-Methoxy-3-trifluoromethyl-phenylamine

[0167] 3,5-Dichloro-4-methoxy-2-methyl-phenylamine

[0168] 5-Chloro-2-ethoxy-4-methoxy-phenylamine

[0169] 5-Chloro-4-ethoxy-2-methoxy-phenylamine

[0170] 5-Iodo-2,4-dimethoxy-phenylamine

[0171] 3,5-Diiodo-2,4-dimethoxy-phenylamine

[0172] 3,5-Dibromo-2,4-dimethoxy-phenylamine

[0173] 5-Chloro-2-methoxy-4-methyl-phenylamine

[0174] 2-Chloro-N(1),N(1)-dimethyl-benzene-1,4-diamine

[0175] 3-Chloro-4-piperidin-1-yl-phenylamine

[0176] 3-Chloro-4-pyrrolidin-1-yl-phenylamine

[0177] N(1 )-Benzyl-2-chloro-benzene-1,4-diamine

[0178] 3-Chloro-4-(4-methyl-piperazin-1-yl)-phenylamine

[0179]2-Chloro-N(1)-methyl-N(1)-(1-methyl-piperidin-4-yl)-benzene-1,4-diamine

[0180]2-Chloro-N(1)-methyl-N(1)-(1-methyl-pyrrolidin-3-yl)-benzene-1,4-diamine

[0181] 2-Chloro-N(1)-methyl-N(1)-phenyl-benzene-1,4-diamine

[0182]N(1)-(1-Benzyl-pyrrolidin-3-yl)-2-chloro-N(1)-methyl-benzene-1,4-diamine

[0183] 2-Chloro-N(1)-cyclopentyl-N(1)-methyl-benzene-1,4-diamine

[0184] 2-[(4-Amino-2-chloro-phenyl)-(2-hydroxy-ethyl)-amino]-ethanol

[0185] 2-Chloro-N(1)-hexyl-N(1)-methyl benzene-1,4-diamine

[0186] 2-Chloro-N(1 )-isobutyl-N(1)-methyl-benzene-1,4-diamine

[0187] 2-[(4-Amino-2-chloro-phenyl)-methyl-amino]-ethanol

[0188]2-Chloro-N(1)-(3-dimethylamino-propyl)-N(1)-methyl-benzene-1,4-diamine

[0189]2-Chloro-N(1)-(2-dimethylamino-ethyl)-N(1)-methyl-benzene-1,4-diamine

[0190] 2-Chloro-N(1)-(2-dimethylamino-ethyl)-benzene-1,4-diamine

[0191] N(1)-(1-Benzyl-piperidin-4-yl)-2-chloro-benzene-1,4-diamine

[0192] 2-Chloro-N(1)-(2-methoxy-ethyl)-N(1)-methyl-benzene-1,4-diamine

[0193] 2-Chloro-N(1)-(3-dimethylamino-propyl)-benzene-1,4-diamine

[0194] N(1)-(1-Benzyl-pyrrolidin-3-yl)-2-chloro-benzene-1,4-diamine

[0195] 3-Chloro-4-(1-methyl-piperidin-4-yloxy)-phenylamine

[0196] 3-Chloro-4-(2-dimethylamino-ethoxy)-phenylamine

[0197] 3-Chloro-4-(3-dimethylamino-propoxy)-phenylamine

[0198] 3-Chloro-4-(1-methyl-pyrrolidin-3-yloxy)-phenylamine

[0199] 3-Chloro-4-cyclohexyloxy-phenylamine

EXAMPLE 2 (METHOD 1B) 4-Bromo-2,4-dimethoxy-phenylamine

[0200] A suspension of 4-bromo-2,4-dimethoxy-nitrobenzene (0.48 g) andiron powder (0.42 g) in acetic acid (10 mL) and ethanol (10 mL) isheated to 120° C. for approximately 5 hours. The mixture is then cooled,filtered, and concentrated under reduced pressure. Water is added andthe mixture is cooled in an ice bath and neutralized with solidpotassium carbonate and then extracted with dichloromethane. Theseorganic extracts are washed with saturated aqueous sodium chloride,dried over anhydrous sodium sulfate, concentrated under reducedpressure, then chromatographed over silica gel (20% ethyl acetate inhexanes is used as the eluant) to provide the desired compound as anamber oil.

EXAMPLE 3 (METHOD 1C) (4-Amino-2,6-dichloro-phenoxy)-acetic AcidTert-Butyl Ester

[0201] A soution of (4-nitro-2,6-dichloro-phenoxy)-acetic acidtert-butyl ester (1 g) in ethanol (17 mL) and water (8.6 mL) is treatedwith iron powder (0.861 g) and ammonium chloride (86 mg) and the mixtureis heated to reflux for approximately 1 hour. The mixture is thenfiltered and concentrated under reduced pressure. The resulting oil ispartitioned between water and ethyl acetate, and the organic phase isthen washed with saturated aqueous sodium chloride, dried over anhydroussodium sulfate, and concentrated under reduced pressure to provide thedesired compound as a pale yellow solid.

[0202] Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

[0203] 4-Chloro-benzene-1,2-diamine

[0204] N-(4-Amino-2-chloro-phenyl)-acetamide

[0205] (4-Amino-2,6-dichloro-phenoxy)-acetonitrile

[0206] (4-Amino-2,6-dichloro-phenoxy)-acetic acid tert-butyl ester

[0207] (2-Amino-4-chloro-5-methoxy-phenoxy)-acetonitrile

[0208] (4-Amino-2-chloro-5-methoxy-phenoxy)-acetic acid methyl ester

[0209] (4-Amino-2-chloro-5-methoxy-phenoxy)-acetic acid tert-butyl ester

[0210] (2-Amino-4-chloro-5-methoxy-phenoxy)-acetic acid tert-butyl ester

[0211] N(1)-Benzyl-4-chloro-5-methoxy-benzene-1,2-diamine

[0212] N-(4-Amino-2-chloro-phenyl)-2-fluoro-benzamide

[0213] N-(4-Amino-5-chloro-2-hydroxy-phenyl)-acetamide

[0214] N-(4-Amino-5-chloro-2-hydroxy-phenyl)-2-fluoro-benzamide

[0215] Furan-2-carboxylic acid (4-amino-2-chloro-phenyl)-amide

[0216] (4-Amino-2-chloro-phenyl)-carbamic acid ethyl ester

[0217] N-(4-Amino-5-chloro-2-methyl-phenyl)-acetamide

[0218] N-(4-Amino-5-chloro-2-methyl-phenyl)-2-fluoro-benzamide

[0219] Furan-2-carboxylic acid (4-amino-5-chloro-2-methyl-phenyl)amide

[0220] N-(4-Amino-3-chloro-phenyl)-2-fluoro-benzamide Furan-2-carboxylicacid (4-amino-3-chloro-phenyl)-amide

[0221] N-(4-Amino-2-chloro-phenyl)-2-dimethylamino-acetamide

[0222] N-(4-Amino-2-chloro-phenyl)-2-piperidin-1-yl-acetamide

[0223] N-(4-Amino-2-chloro-phenyl)-2-morpholin-4-yl-acetamide

[0224] N-(4-Amino-2-chloro-phenyl)-methanesulfonamide

[0225] N-(4-Amino-2-chloro-phenyl)-benzamide

[0226] N-(4-Amino-2-chloro-phenyl)-2-diethylamino-acetamide

[0227] N-(4-Amino-2-chloro-phenyl)-2-pyrrolidin-1-yl-acetamide

[0228] N-(4-Amino-2-chloro-phenyl)-2-azepan-1-yl-acetamide

[0229] N-(4-Amino-2-chloro-phenyl)-2-(2-methyl-piperidin-1-yl)-acetamide

[0230] N-(4-Amino-2-chloro-phenyl)-2-(3-methyl-piperidin-1-yl)-acetamide

[0231] 3-Chloro-benzene-1,2-diamine

[0232] 4-Chloro-N,N-dimethyl-benzene-1,2-diamine

EXAMPLE 4 (METHOD 1D) 3,5-Dichloro-4-phenoxy-phenylamine

[0233] To a slurry of 3,5-dichloro-4-phenoxy-nitrobenzene (6.1 g) andtin powder (12 g) is added dropwise concentrated hydrochloric acid (60mL). Ethanol (60 mL) is added and the mixture is heated to reflux forapproximately 1 hour. The mixture is then cooled in an ice bath andbasified by addition of solid sodium hydroxide. The resulting suspensionis filtered through a pad of diatomaceous earth and extracted threetimes with ethyl acetate. The combined organic extracts are then washedwith saturated aqueous sodium chloride, dried over anhydrous magnesiumsulfate, and concentrated under reduced pressure to provide the desiredproduct as a yellow solid.

[0234] Recrystallization from ethyl acetate-hexanes provided the productas a pale yellow solid.

[0235] Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

[0236] 1-Furan-2-yl-ethylamine

[0237] 3-Chloro-4-isopropoxy-phenylamine

[0238] 2-Butoxy-5-chloro-4-methoxy-phenylamine

[0239] 3,5-Dichloro-2-methoxy-4-methyl-phenylamine

[0240] 2-Benzyloxy-5-chloro-4-methoxy-phenylamine

[0241] 4-Benzyloxy-5-chloro-2-methoxy-phenylamine

[0242] 5-Fluoro-2,4-dimethoxy-phenylamine

[0243] (4-Amino-2,6-dichloro-phenoxy)-acetic acid ethyl ester

[0244] 3,5-Dichloro-4-phenoxy-phenylamine

[0245] 2-(4-Amino-2-chloro-5-methoxy-phenoxy)-acetamide

[0246] (4-Amino-2-chloro-5-methoxy-phenoxy)-acetonitrile

[0247] 2-(2-Amino-4-chloro-5-methoxy-phenoxy)-ethanol

[0248] 2-(4-Amino-2-chloro-5-methoxy-phenoxy)-ethanol

[0249] 4-(4-Amino-2-chloro-5-methoxy-phenoxy)-butyronitrile

[0250] 4-Amino-2-chloro-5-methoxy-phenol

[0251] 2-Amino-4-chloro-5-methoxy-phenol

[0252] 5-Chloro-4-methoxy-2-morpholin-4-yl-phenylamine

[0253] 4-Chloro-5-methoxy-N(1),N(1)-dimethyl-benzene-1,2-diamine

[0254] 5-Chloro-4-methoxy-2-piperidin-1-yl-phenylamine

[0255] 5-Chloro-4-methoxy-2-pyrrolidin-1-yl-phenylamine

[0256] 2-Chloro-N(1)-cyclohexyl-N(1)-methyl-benzene-1,4-diamine

[0257] N(2)-Benzyl-4-methoxy-benzene-1,2-diamine

[0258] 2-(4-Amino-2-chloro-phenoxy)-ethanol

[0259] 2-Chloro-N(1)-cyclohexyl-N(1)-ethyl-benzene-1,4-diamine

[0260] 4-Butoxy-3-chloro-phenylamine

[0261] (4-Amino-2-chloro-phenoxy)-acetonitrile

[0262] 2-Chloro-N(1)-cyclohexyl-benzene-1,4-diamine

[0263] 2-Chloro-N(1),N(1)-dipropyl-benzene-1,4-diamine

[0264] 3-Chloro-4-(2,2,2-trifluoro-ethoxy)-phenylamine

[0265] 3-Chloro-4-(octahydro-quinolin-1-yl)-phenylamine

[0266] N(1)-Allyl-2-chloro-N(1)-cyclohexyl-benzene-1,4-diamine

[0267] N-(4-Amino-2-methoxy-5-methyl-phenyl)-2-fluoro-benzamide

[0268] Furan-2-carboxylic acid (4-amino-2-methoxy-5-methyl-phenyl)amide

[0269] N-(4-Amino-naphthalen-1-yl)-2-fluoro-benzamide

[0270] 3-Chloro-N,N-dimethyl-benzene-1,2-diamine

[0271] 3-Chloro-4-propoxy-phenylamine

[0272] 3-Iodo-4-methoxy-phenylamine

[0273] 3-Chloro-2,4-dimethoxy-aniline

[0274] 3-Bromo-4-methoxyphenylamine

[0275] 3-Chloro-4-ethoxy-phenylamine

EXAMPLE 5 (Method 1E) (4-Amino-phenyl)-Carbamic Acid Isobutyl Ester

[0276] To a solution of N-(4-Nitro-phenyl)-isobutyrlamide (2.0 g) in 100mL ethylene glycol monomethyl ether (100 mL) is added 10% palladium oncarbon (275 mg). The mixture is hydrogenated for 2 hours at roomtemperature under 30 psi of hydrogen on a Parr hydrogenation apparatus.The catalyst is then removed by filtration through diatomaceous earthand the filtrate is evaporated to dryness under reduced pressure byazeotroping three times with heptane. Trituration of the residue withheptane provides the desired product as a white solid.

[0277] Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

[0278] 2-Methyl-3H-benzoimidazol-5-ylamine

[0279] N-(4-Amino-phenyl)-formamide

[0280] 1H-Benzoimidazol-5-ylamine

[0281] (4-Amino-phenyl)-carbamic acid isobutyl ester

[0282] N-(4-Amino-phenyl)-isobutyramide

[0283] N-(5-Amino-pyridin-2-yl)-2-methyl-benzamide

[0284] Furan-2-carboxylic acid (5-amino-pyridin-2-yl)-amide

[0285] N-(5-Amino-pyridin-2-yl)-2-fluoro-benzamide

[0286] [6-(2,2,2-Trifluoro-acetylamino)-pyridin-3-yl]-carbamic acidtert-butyl ester

[0287] N-(5-Amino-pyridin-2-yl)-2,2,2-trifluoro-acetamide

[0288] (4-Amino-benzyl)-carbamic acid tert-butyl ester

[0289] 2-(3,5-Bis-trifluoromethyl-phenyl)-ethylamine

[0290] 1-tert-Butyl-1H-imidazol-2-ylamine

[0291] 3-(3-Dimethylamino-propyl)-5-trifluoromethyl-phenylamine

EXAMPLE 6 (METHOD 1F) N-(4-Amino-2-methylphenyl)-2-fluorobenzamide

[0292] A mixture of 2-fluoro-N-(2-methyl-4-nitrophenyl)benzamide (4.55g), cyclohexene (30 mL), ethanol (70 mL), water (30 mL) and 10%palladium on charcoal (3 g) is heated at reflux for 30 minutes. Themixture is filtered through diatomaceous earth and concentrated underreduced pressure. The resulting oil is dissolved in 50 mL of ethylacetate and cooled at 4° C. for 12 hours. Filtration provides theproduct as a tan solid.

[0293] Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

[0294] N-(4-Amino-2-methyl-phenyl)-acetamide

[0295] 2-Methyl-benzooxazol-6-ylamine

[0296] N-(4-Amino-3-methoxy-phenyl)-acetamide

[0297] 2-Acetylamino-5-amino-benzoic acid

[0298] N-(4-Amino-phenyl)-acetamide

[0299] [4-(3-Amino-benzoylamino)-phenyl]-carbamic acid tert-butyl ester

[0300] [4-(2-Amino-benzoylamino)-phenyl]-carbamic acid tert-butyl ester

[0301] N-(4-Amino-2-cyano-phenyl)-acetamide

[0302] N-(4-Amino-2,5-dimethoxy-phenyl)-2-fluoro-benzamide

[0303] Furan-2-carboxylic acid (4-amino-2,5-dimethoxy-phenyl)-amide

[0304] N-(4-Amino-2-cyano-phenyl)-2-fluoro-benzamide

[0305] Furan-2-carboxylic acid (4-amino-2-methoxy-phenyl)-amide

[0306] N-(4-Amino-2-methoxy-phenyl)-2-fluoro-benzamide

[0307] N-(4-Amino-2-methoxy-5-methyl-phenyl)-acetamide

[0308] N-(4-Amino-2-benzoyl-phenyl)-acetamide

[0309] N-(4-Amino-2-benzoyl-phenyl)-2-fluoro-benzamide

[0310] Furan-2-carboxylic acid (4-amino-2-benzoyl-phenyl)-amide

[0311] N-(4-Amino-3-methyl-phenyl)-acetamide

[0312] N-(4-Amino-3-methyl-phenyl)-2-fluoro-benzamide

[0313] Furan-2-carboxylic acid (4-amino-3-methyl-phenyl)-amide

[0314] 5-Amino-2-[(2-fluorobenzoyl)amino]-N-phenylbenzamide

[0315] Furan-2-carboxylic acid (4-amino-2-phenylcarbamoyl-phenyl)amide

[0316] N-(4-Amino-naphthalen-1-yl)-acetamide

[0317] Furan-2-carboxylic acid (4-amino-naphthalen-1-yl)-amide

[0318] N-(4-Amino-2-trifluoromethyl-phenyl)-acetamide

[0319] Furan-2-carboxylic acid (4-amino-2-cyano-phenyl)-amide

[0320] Furan-2-carboxylic acid (4-amino-2-trifluoromethyl-phenyl)-amide

[0321] N-(4-Amino-2-methyl-phenyl)-2-fluoro-benzamide

[0322] Furan-2-carboxylic acid (4-amino-2-methyl-phenyl)-amide

[0323] 5-Amino-2-(2-fluoro-benzoylamino)-benzoic acid5-Amino-2-[(furan-2-carbonyl)-amino]-benzoic acid

[0324] N-(4-Amino-2-cyano-phenyl)-2,2,2-trifluoro-acetamide

[0325] N-(4-Amino-3-methyl-phenyl)-2,6-difluoro-benzamide

[0326] N-(4-Amino-3-trifluoromethyl-phenyl)-acetamide

[0327] N-(4-Amino-3-trifluoromethyl-phenyl)-2-fluoro-benzamide

[0328] N-(4-Amino-2-trifluoromethyl-phenyl)-2,2,2-trifluoro-acetamide

[0329] N-(4-Amino-2-methoxy-phenyl)-2,2,2-trifluoro-acetamide

[0330]N-(4-Amino-2-trifluoromethyl-phenyl)-2-fluoro-N-(2-fluoro-benzoyl)-benzamide

[0331] N-(4-Amino-2-trifluoromethyl-phenyl)-2-fluoro-benzamide

EXAMPLE 7 (METHOD 1G)N-(4-Amino-2-chlorophenyl)-2-thiomorpholino-4-yl-acetamide

[0332] A solution ofN-(2-chloro-4-nitrophenyl)-2-thiomorpholino-4-yl-acetamide (3.02 g) inethanol (200 mL) is added to a solution of sodium thiosulfate (12 g) inwater (60 mL). The mixture is heated at reflux for 12 hours, cooled andpoured into water. The mixture is then extracted with ethyl acetate. Theethyl acetate solution is washed twice with saturated aqueous sodiumchloride, dried over anhydrous potassium carbonate, filtered through apad of diatomaceous earth and concentrated under reduced pressure togive an oil. Toluene is added and the solution chilled to give thedesired product as a light orange crystalline solid.

[0333] Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

[0334] N-(4-Amino-2-chloro-phenyl)-2-thiomorpholin-4-yl-acetamide

[0335] N-(4-Amino-2-chloro-phenyl)-2-dipropylamino-acetamide

EXAMPLE 8 (METHOD 2A) (3-Chloro-4-iodo-phenyl)-carbanic Acid Tert-ButylEster

[0336] To a solution of 3-chloro-4-iodo-aniline (10 g) intetrahydrofuran (40 mL) containing diiso-propylethylamine (6.9 mL) isadded di-tert-butyl-dicarbonate (8.6 g) and the mixture is heated toreflux. After approximately 15 hours additional portions ofdilsopropylethylamine (6.9 mL) and di-tert-butyl-dicarbonate (21 g) isadded and heating is continued for approximately 24 hours. The solutionis then cooled, concentrated under reduced pressure, diluted with ethylacetate, and washed successively three times with 5% aqueoushydrochloric acid then once with saturated aqueous sodium chloride. Thesolution is dried over anhydrous sodium sulfate then concentrated underreduced pressure to provide the desired crude product as a brown oil.Crystallization is induced by addition of hexanes, and the collectedsolid material is recrystallized from hexanes to give the desiredproduct as a white solid.

[0337] Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

[0338] N′-(4-Nitro-benzoyl)-hydrazinecarboxylic acid tert-butyl ester

[0339] (3-Chloro-4-iodo-phenyl)-carbamic acid tert-butyl ester

[0340] (4-Bromo-3-chloro-phenyl)-carbamic acid tert-butyl ester

[0341] (3-Chloro-4-vinyl-phenyl)-carbamic acid tert-butyl ester

[0342] (3-Chloro-4-methylsulfanyl-phenyl)-carbamic acid tert-butyl ester

[0343] (4-Amino-3-chloro-phenyl)-carbamic acid tert-butyl ester

[0344] (4-Chloro-2-nitro-phenyl)-carbamic acid tert-butyl ester

[0345] (3-tert-Butoxycarbonylamino-5-chloro-phenyl)-carbamic acidtert-butyl ester

[0346] (4-Nitro-benzyl)-carbamic acid tert-butyl ester

[0347] (3-Bromo-5-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester

[0348] (2-Amino-3-chloro-5-trifluoromethyl-phenyl)-carbamic acidtert-butyl ester

EXAMPLE 9 (METHOD 2B) (3-Chloro-4-vinyl-phenyl)-carbamicAcid2-trimethylsilanyl-ethyl Ester

[0349] To a solution of 3-chloro-4-vinyl-phenylamine (3.4 g) inN,N-dimethylformamide (44 mL) containing diisopropylethylamine (5.8 mL)is added 1-[2-(trimethylsilyl)-ethoxycarbonyl-oxy]benzotriazole (7.1 g)and the mixture is stirred at room temperature under an atmosphere ofargon for three days. The solution is then diluted with water andextracted three times with diethyl ether. The combined organic extractsare washed successively with water, saturated aqueous sodium chloride,dried over anhydrous magnesium sulfate, and concentrated under reducedpressure. The resulting residue is chromatographed over silica gel (10%ethyl acetate in hexanes is used as the eluant) to provide the desiredproduct as a yellow oil.

EXAMPLE 10 (METHOD 2C) [4-(2-Fluoro-benzoylamino)-phenyl]-carbamic AcidTert-Butyl Ester

[0350] To a solution of mono-N-(t-butoxycarbonyl)-1,4-phenylenediamine(1.58 g) and triethylamine (1.50 mL) in 25 mL of dichloromethane isadded o-fluorobenzoyl chloride (1.20 g). A solid formed immediatelyforms and is filtered and washed with fresh solvent to yield a whitesolid, 1.90 g.

[0351] Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

[0352] N-(3-Methoxy-4-nitro-phenyl)-acetamide

[0353] N-(4-Amino-phenyl)-isobutyrlamide

[0354] 2,2,2-Trifluoro-N-(2-methoxy-4-nitro-phenyl)-acetamide

[0355] [4-(2-Methyl-benzoylamino)-phenyl]-carbamic acid tert-butyl ester

[0356] Acetic acid 2-(4-tert-butoxycarbonylamino-phenylcarbamoyl)-phenylester

[0357] [4-(4-Fluoro-benzoylamino)-phenyl]-carbamic acid tert-butyl ester

[0358] [4-(3-Fluoro-benzoylamino)-phenyl]-carbamic acid tert-butyl ester

[0359] [4-(2-Fluoro-benzoylamino)-phenyl]-carbamic acid tert-butyl ester

[0360] [4-(2-Methoxy-benzoylamino)-phenyl]-carbamic acid tert-butylester

[0361] [4-(3-Methoxy-benzoylamino)-phenyl]-carbamic acid tert-butylester

[0362] [4-(4-Methoxy-benzoylamino)-phenyl]-carbamic acid tert-butylester

[0363] [4-(2,2-Dimethyl-propionylamino)-phenyl]-carbamic acid tert-butylester

[0364] [4-(2-Bromo-acetylamino)-phenyl]-carbamic acid tert-butyl ester

[0365] [4-(2,2,2-Trifluoro-acetylamino)-phenyl]-carbamic acid tert-butylester

[0366] (4-Benzoylamino-phenyl)-carbamic acid tert-butyl ester

[0367] (4-Methanesulfonylamino-phenyl)-carbamic acid'tert-butyl ester

[0368] (4-Phenylacetylamino-phenyl)-carbamic acid tert-butyl ester

[0369] (4-[(Thiophene-2-carbonyl)-amino]-phenyl)-carbamic acidtert-butyl ester

[0370] [4-(3-Nitro-benzoylamino)-phenyl]-carbamic acid tert-butyl ester

[0371] [4-(3-Acetylamino-benzoylamino)-phenyl]-carbamic acid tert-butylester

[0372] [4-(3-Methanesulfonylamino-benzoylamino)-phenyl]-carbamic acidtert-butyl ester

[0373] Ethyl[3-[[[4-[[(1,1-dimethylethoxy]carbonylamino]phenyl]amino]carbonyl]phenyl]carbamate

[0374] [4-(2-Trifluoromethyl-benzoylamino)-phenyl]-carbamic acidtert-butyl ester

[0375] [4-(2,6-Difluoro-benzoylamino)-phenyl]-carbamic acid tert-butylester

[0376] [4-(2-Chloro-benzoylamino)-phentyl]-carbamic acid tert-butylester

[0377] [4-(2-Bromo-benzoylamino)-phenyl]-carbamic acid tert-butyl ester

[0378] [4-(2-Nitro-benzoylamino)-phenyl]-carbamic acid tert-butyl ester

[0379] {4-[(Benzo[b]thiophene-2-carbonyl)-amino]-phenyl}-carbamic acidtert-butyl ester

[0380] {4-[(Pyridine-4-carbonyl)-amino]-phenyl}-carbamic acid tert-butylester

[0381] {4-[(Naphthalene-2-carbonyl)-amino]-phenyl}-carbamic acidtert-butyl ester

[0382] {4-[(Naphthalene-1-carbonyl)-amino]-phenyl}-carbamic acidtert-butyl ester

[0383] {4-[(3-Bromo-thiophene-2-carbonyl)-amino]-phenyl}-carbamic acidtert-butyl ester

[0384] {4-[(Biphenyl-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butylester

[0385] N-(4-tert-Butoxycarbonylamino-phenyl)-phthalamic acid

[0386] [4-(2,3-Difluoro-benzoylamino)-phenyl]-carbamic acid tert-butylester

[0387] [4-(2,5-Difluoro-benzoylamino)-phenyl]-carbamic acid tert-butylester

[0388] [4-(2,4-Difluoro-benzoylamino)-phenyl]-carbamic acid tert-butylester

[0389] [4-(2-Acetylamino-benzoylamino)-phenyl]-carbamic acid tert-butylester

[0390] [4-(2-Methanesulfonylamino-benzoylamino)-phenyl]-carbamic acidtert-butyl ester

[0391] [4-(2,3,4-Trifluoro-benzoylamino)-phenyl]-carbamic acidtert-butyl ester

[0392] [4-(2,3,4,5,6-Pentafluoro-benzoylamino)-phenyl]-carbamic acidtert-butyl ester

[0393] N-(4-tert-Butoxycarbonylamino-phenyl)-isophthalamic acid methylester

[0394]2-Methylsulfanyl-N-[4-(2,2,2-trifluoro-acetylamino)-phenyl]-benzamide

[0395] [4-(3-Benzyloxy-benzoylamino)-phenyl]-carbamic acid tert-butylester

[0396] [4-(3-Butoxy-benzoylamino)-phenyl]-carbamic acid tert-butyl ester

[0397] (4-[(5-Difluoromethyl-furan-2-carbonyl)-amino]-phenyl)-carbamicacid tert-butyl ester

[0398] {4-[(Thiophene-3-carbonyl)-amino]-phenyl}-carbamic acidtert-butyl ester

[0399] {4-[(5-Methyl-furan-2-carbonyl)-amino]-phenyl}-carbamic acidtert-butyl ester

[0400] {4-[(5-Bromo-furan-2-carbonyl)-amino]-phenyl}-carbamic acidtert-butyl ester

[0401] (4-Hexanoylamino-phenyl)-carbamic acid tert-butyl ester

[0402] [4-(2-Thiophen-2-yl-acetylamino)-phenyl]-carbamic acid tert-butylester

[0403] {4-[(Pyridine-3-carbonyl)-amino]-phenyl}-carbamic acid tert-butylester

[0404] {4-[(4-Bromo-furan-2-carbonyl)-amino]-phenyl}-carbamic acidtert-butyl ester

[0405] {4-[(Furan-3-carbonyl)-amino]-phenyl}-carbamic acid tert-butylester

[0406] (4-Phenoxycarbonylamino-phenyl)-carbamic acid tert-butyl ester

[0407] {4-[(Benzo[1,3]dioxole-4-carbonyl)-amino]-phenyl}-carbamic acidtert-butyl ester

[0408] [4-(3-Trifluoromethoxy-benzoylamino)-phenyl]-carbamic acidtert-butyl ester

[0409] N-(2,5-Dimethoxy-4-nitro-phenyl)-2-fluoro-benzamide

[0410] (4-[(Furan-2-carbonyl)-amino]-phenyl)-carbamic acid tert-butylester

[0411] [4-(2-Phenoxy-acetylamino)-phenyl]-carbamic acid tert-butyl ester

[0412] {4-[(5-Nitro-furan-2-carbonyl)-amino]-phenyl}-carbamic acidtert-butyl ester {4-[(5-Chloro-furan-2-carbonyl)-amino]-phenyl}-carbamicacid tert-butyl ester

[0413] {4-[(3-Methyl-furan-2-carbonyl)-amino]-phenyl}-carbamic acidtert-butyl ester

[0414] [4-(2-Methoxy-acetylamino)-phenyl]-carbamic acid tert-butyl ester

[0415]{4-[(4-Furan-3-yl-[1,2,3]thiadiazole-5-carbonyl)-amino]-phenyl}-carbamicacid tert-butyl ester

[0416] {4-[(5-tert-Butyl-furan-2-carbonyl)-amino]-phenyl}-carbamic acidtert-butyl ester

[0417]N-[3-Cyano-4-(2,2,2-trifluoro-acetylamino)-phenyl]-2-fluoro-benzamide

[0418] Furan-2-carboxylic acid[3-cyano-4-(2,2,2-trifluoro-acetylamino)-phenyl]amide

[0419] N-(4-Acetylamino-2-cyano-phenyl)-2,2,2-trifluoro-acetamide

[0420] 2,2,2-Trifluoro-N-(4-nitro-2-trifluoromethyl-phenyl)-acetamide

[0421]N-(4-Acetylamino-2-trifluoromethyl-phenyl)-2,2,2-trifluoro-acetamide

[0422]2-Fluoro-N-[4-(2,2,2-trifluoro-acetylamino)-3-trifluoromethyl-phenyl]benzamide

[0423] Furan-2-carboxylic acid[4-(2,2,2-trifluoro-acetylamino)-3-trifluoromethyl-phenyl]amide

[0424] 2-Fluoro-N-(2-methyl-benzooxazol-6-yl)-benzamide

[0425] 4-(2-Fluoro-benzoylamino)-2-hydroxy-benzoic acid phenyl ester

[0426] {4-[(Isoxazole-5-carbonyl)-amino]-phenyl}-carbamic acidtert-butyl ester

[0427] N-(4-Acetylamino-2-methoxy-phenyl)-2,2,2-trifluoro-acetamide

[0428]2-Fluoro-N-[3-methoxy-4-(2,2,2-trifluoro-acetylamino)-phenyl]benzamide

[0429]2-Fluoro-N-(2-fluoro-benzoyl)-N-(4-nitro-2-trifluoromethyl-phenyl)benzamide

[0430] {4-[(1H-Pyrazole-4-carbonyl)-amino]-phenyl}-carbamic acidtert-butyl ester

[0431] {4-[(1H-Imidazole-4-carbonyl)-amino]-phenyl}-carbamic acidtert-butyl ester

[0432]{4-[(5-Methyl-[1,2,3]thiadiazole-4-carbonyl)-amino]-phenyl}-carbamicacid tert-butyl ester

[0433]{4-[(5-Furan-3-yl-[1,2,3]thiadiazole-4-carbonyl)-amino]-phenyl}-carbamicacid tert-butyl ester

[0434] 2,2,2-Trifluoro-N-(5-nitro-pyridin-2-yl)-acetamide

[0435] {4-[(1-Methyl-1H-pyrazole-4-carbonyl)-amino]-phenyl}-carbamicacid tert-butyl ester

[0436] 4-(2-Fluoro-benzoylamino)-2-hydroxy-benzoic acid methyl ester

[0437] N-(5-Chloro-2,4-dimethoxy-phenyl)-oxalamic acid

[0438] Isoxazole-5-carboxylic acid (4-amino-phenyl)-amide

[0439] 2-Fluoro-N-(4-nitro-benzyl)-benzamide

[0440] Furan-2-carboxylic acid 4-nitro-benzylamide

[0441]N-[3-Chloro-5-(2,2,2-trifluoro-acetylamino)-phenyl]-2,2,2-trifluoro-acetamide

[0442] N-(3-Amino-5-chloro-phenyl)-2,2,2-trifluoro-acetamide

[0443] [4-(2-Fluoro-benzoylamino)-benzyl]-carbamic acid tert-butyl ester

[0444] [4-(2,6-Difluoro-benzoylamino)-benzyl]-carbamic acid tert-butylester

[0445] 2,6-Difluoro-N-(4-nitro-benzyl)-benzamide

[0446] {4-[(Furan-2-carbonyl)-amino]-benzyl}-carbamic acid tert-butylester

[0447] N-(3-Amino-5-chloro-phenyl)-acetamide

[0448] [4-(3-Chloro-benzoylamino)-phenyl]-carbamic acid tert-butyl ester

[0449] [4-(4-Chloro-benzoylamino)-phenyl]-carbamic acid tert-butyl ester

[0450] [4-(4-Dimethylamino-benzoylamino)-phenyl]-carbamic acidtert-butyl ester

[0451] (4-Benzenesulfonylamino-phenyl)-carbamic acid tert-butyl ester

[0452] [4-(3-Trifluoromethyl-benzoylamino)-phenyl]-carbamic acidtert-butyl ester

[0453] 2,2,2-Trifluoro-N-(5-nitro-pyrimidin-2-yl)-acetamide

EXAMPLE 11(METHOD 2D) 2-Chloro-N-(2-chloro-4-nitrophenyl)acetamide

[0454] A solution of 2-chloro-4-nitroaniline (19.0 g) and chloroacetylchloride (30 mL) in tetrahydrofuran (150 mL) is heated at reflux for 1hour. The solution is cooled and concentrated under reduced pressure,giving a wet yellow solid. Ether (250 mL) is added and the yellow solidis collected.

[0455] Using the above procedure and appropriate starting materias thefollowing compounds were prepared:

[0456] N-(4-Nitro-3-trifluoromethyl-phenyl)-acetamide

[0457] (2-Chloro-4-nitro-phenyl)-carbamic acid ethyl ester

[0458] 2-Acetylamino-5-nitro-benzoic acid

[0459] Furan-2-carboxylic acid (5-chloro-2-hydroxy-4-nitro-phenyl)-amide

[0460] Furan-2-carboxylic acid (2-methyl-4-nitro-phenyl)-amide

[0461] Furan-2-carboxylic acid (2-methoxy-4-nitro-phenyl)-amide

[0462] N-(2-Chloro-4-nitro-phenyl)-benzamide

[0463] 2-Methoxy-N-(4-nitro-phenyl)-acetamide

[0464] N-(4-Nitro-phenyl)-acrylamide

[0465] N-(4-Nitro-phenyl)-isobutyrlamide

[0466] [4-)acryloylamino)-phenyl]carbamic acid tert-butyl ester

[0467] (4-Nitro-phenyl)-carbamic acid isobutyl ester

[0468] [1,2,3]Thiadiazole-4-carboxylic acid (5-nitro-pyridin-2-yl)-amide

[0469] Furan-2-carboxylic acid (5-nitro-pyridin-2-yl)-amide

[0470] 2-Fluoro-N-(5-nitro-pyridin-2-yl)-benzamide

[0471] N-(2-Chloro-4-nitro-phenyl)-2-fluoro-benzamide

[0472] Furan-2-carboxylic acid (2,5-dimethoxy-4-nitro-phenyl)-amide

[0473] N-(2-Cyano-4-nitro-phenyl)-2-fluoro-benzamide

[0474] 2-Fluoro-N-(2-methoxy-4-nitro-phenyl)-benzamide

[0475] 2-Methyl-N-(5-nitro-pyridin-2-yl)-benzamide

[0476] Furan-2-carboxylic acid (2-methoxy-5-methyl-4-nitro-phenyl)-amide

[0477] 2-Fluoro-N-(2-methoxy-5-methyl-4-nitro-phenyl)-benzamide

[0478] N-(2-Benzoyl-4-nitro-phenyl)-acetamide

[0479] N-(2-Benzoyl-4-nitro-phenyl)-2-fluoro-benzamide

[0480] Furan-2-carboxylic acid (2-benzoyl-4-nitro-phenyl)-amide

[0481] N-(3-Methyl-4-nitro-phenyl)-acetamide

[0482] 2-Fluoro-N-(3-methyl-4-nitro-phenyl)-benzamide

[0483] Furan-2-carboxylic acid (3-methyl-4-nitro-phenyl)-amide

[0484] 2-Acetylamino-5-nitro-N-phenyl-benzamide

[0485] 2-[(2-Fluorobenzoyl)amino]-5-nitro-N-phenylbenzamide

[0486] Furan-2-carboxylic acid (4-nitro-2-phenylcarbamoyl-phenyl)-amide

[0487] 2-Fluoro-N-(4-nitro-naphthalen-1-yl)-benzamide

[0488] Furan-2-carboxylic acid (4-nitro-naphthalen-1-yl)-amide

[0489] N-(5-Chloro-2-hydroxy-4-nitro-phenyl)-acetamide

[0490] N-(5-Chloro-2-hydroxy-4-nitro-phenyl)-2-fluoro-benzamide

[0491] Furan-2-carboxylic acid (2-chloro-4-nitro-phenyl)-amide

[0492] N-(4-Nitro-2-trifluoromethyl-phenyl)-acetamide

[0493] Furan-2-carboxylic acid (2-cyano-4-nitro-phenyl)-amide

[0494] 2-Fluoro-N-(4-nitro-2-trifluoromethyl-phenyl)-benzamide

[0495] Furan-2-carboxylic acid (4-nitro-2-trifluoromethyl-phenyl)-amide

[0496] 2-Fluoro-N-(2-methyl-4-nitro-phenyl)-benzamide

[0497] N-(5-Chloro-2-methyl-4-nitro-phenyl)-2-fluoro-benzamide

[0498] Furan-2-carboxylic acid (5-chloro-2-methyl-4-nitro-phenyl)-amide

[0499] 2-(2-Fluoro-benzoylamino)-5-nitro-benzoic acid

[0500] 2-[(Furan-2-carbonyl)-amino]-5-nitro-benzoic acid

[0501] N-(3-Chloro-4-nitro-phenyl)-2-fluoro-benzamide

[0502] Furan-2-carboxylic acid (3-chloro-4-nitro-phenyl)-amide

[0503] 2,6-Difluoro-N-(3-methyl-4-nitro-phenyl)-benzamide

[0504] 2-Fluoro-N-(4-nitro-3-trifluoromethyl-phenyl)-benzamide

[0505] Furan-2-carboxylic acid (4-nitro-3-trifluoromethyl-phenyl)-amide

[0506] 2-Chloro-N-(2-chloro-4-nitro-phenyl)-acetamide

[0507] N-(2-Chloro-4-nitrophenyl)methanesulfonamide

[0508] Furan-2-carboxylic acid[3-methoxy-4-(2,2,2-trifluoro-acetylamino)-phenyl]-amide

[0509] N-(2-Chloro-4-nitro-phenyl)-2,2,2-trifluoro-acetamide

EXAMPLE 12{4-[(4-Phenyl-[1,2,3]thiadiazole-5-carbonyl)-amino]-phenyl}-carbamicAcid Tert-Butyl

[0510] A solution of 1-(N-tert-butoxycarbonyl)-1,4-phenylenediamine (0.8g) and 4-phenyl-[1,2,3]thiadiazole-5-carboxylic acid (0.7 g) indichloromethane (10 mL) is treated with triethylamine (1.3 mL) andbenzotriazole-1-yloxy-tris(dimethylamino)-phosphoniumhexa-fluorophosphate (1.6 g). After stirring at room temperature, thereaction is diluted with water and extracted with dichloromethane. Theorganic layer is washed with 0.5 N hydrochloric acid, saturated sodiumbicarbonate, and water then dried over magnesium sulfate, filtered, andconcentrated under reduced pressure to give the desired product.

[0511] Using the above procedure and appropriate starting materials thefollowing compounds were prepared.

[0512] {4-[(1H-Pyrrole-2-carbonyl)-amino]-phenyl}-carbamic acidtert-butyl ester

[0513] {4-[(Pyrazine-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butylester

[0514] {4-[(5-Methyl-thiophene-2-carbonyl)-amino]-phenyl}-carbamic acidtert-butyl ester

[0515] {4-[(1-Methyl-1H-pyrrole-2-carbonyl)-amino]-phenyl}-carbamic acidtert-butyl ester

[0516] {4-[(Quinoline-8-carbonyl)-amino]-phenyl}-carbamic acidtert-butyl ester

[0517] {4-[(Benzofuran-2-carbonyl)-amino]-phenyl}-carbamic acidtert-butyl ester

[0518] {4-[(Isoquinoline-1-carbonyl)-amino]-phenyl}-carbamic acidtert-butyl ester

[0519] {4-[(Quinoline-2-carbonyl)-amino]-phenyl}-carbamic acidtert-butyl ester

[0520] {4-[(Pyridine-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butylester

[0521] {4-[(Isoquinoline-4-carbonyl)-amino]-phenyl}-carbamic acidtert-butyl ester

[0522] {4-[([1,2,3]Thiadiazole-4-carbonyl)-amino]-phenyl}-carbamic acidtert-butyl ester

[0523] {4-[(1H-[1,2,3]Triazole-4-carbonyl)-amino]-phenyl}-carbamic acidtert-butyl ester

[0524] [4-(2-Methylsulfanyl-benzoylamino)-phenyl]-carbamic acidtert-butyl ester

[0525] {4-[(Quinoline-4-carbonyl)-amino]-phenyl}-carbamic acidtert-butyl ester

[0526]{4-[(4-Methyl-[1,2,3]thiadiazole-5-carbonyl)-amino]-phenyl}-carbamicacid tert-butyl ester

[0527]{4-[(4-Phenyl-[1,2,3]thiadiazole-5-carbonyl)-amino]-phenyl}-carbamicacid tert-butyl ester

[0528] {4-[(1H-Indole-2-carbonyl)-ainino]-phenyl}-carbamic acidtert-butyl ester

[0529] [1,2,3]Thiadiazole-4-carboxylic acid 4-nitro-benzylamide

[0530] {4-[([1,2,3]Thiadiazole-4-carbonyl)-amino]-benzyl}-carbamic acidtert-butyl ester

[0531] Acetic acid 4-(4-tert-butoxycarbonylamino-phenylcarbamoyl)-phenylester

[0532] {4-[(Quinoline-6-carbonyl)-amino]-phenyl}-carbamic acidtert-butyl ester

EXAMPLE 13 (METHOD 2F) Acetic Acid2-(4-tert-butoxycarbonylamino-2,6-dichloro-phenoxy)-ethyl Ester

[0533] A solution of [3,5-dichloro-4-(2-hydroxy-ethoxy)-phenyl]-carbamicacid tert-butyl ester (0.85 g) in pyridine (14 mL) is treated withacetic anhydride (1.24 mL) and the mixture is stirred at roomtemperature for 15 hours. The solvent is removed under reduced pressureand the residue dissolved in ethyl acetate. This solution is then washedtwice with 5% aqueous hydrochloric acid, once with saturated aqueoussodium bicarbonate, and then with saturated aqueous sodium chloride. Thesolution is dried over anhydrous magnesium sulfate and the solvent isremoved under reduced pressure to provide the desired product as acolorless oil.

[0534] Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

[0535] Phenylsulfanyl-acetonitrile

[0536] Acetic acid2-(4-tert-butoxycarbonylamino-2,6-dichloro-phenoxy)-ethyl ester

EXAMPLE 14 (METHOD 2G) (3,5-Dichloro-4-hydroxy-phenyl)-carbamic AcidTert-Butyl Ester

[0537] To a solution of 2,6-dichloro-4-amino phenol (9.5 g) intetrahydrofuran (130 mL) is added di-tert-butyl-dicarbonate (11.7 g) andthe mixture is heated to reflux for approximately 15 hours. The solutionis then cooled, concentrated under reduced pressure, diluted with ethylacetate, and washed successively three times with 5% aqueoushydrochloric acid then once with saturated aqueous sodium chloride. Thesolution is dried over anhydrous sodium sulfate then concentrated underreduced pressure to provide the desired crude product. This material isthen triturated with cold dichloromethane to provide the product as awhite solid.

[0538] Using the above procedure and appropriate starting materials thefollowing compound was prepared:

[0539] (3-Amino-5-chloro-phenyl)-carbamic acid tert-butyl ester

EXAMPLE 15 (METHOD 3A) 3,5-Dichloro-4-ethoxy-phenylamine

[0540] Trifluoroacetic acid (5 mL) is added to solid(3,5-dichloro-4-ethoxy-phenyl)-carbamic acid tert-butyl ester (0.97 g)and the mixture is stirred for approximately 45 minutes at roomtemperature. Water is then added, and the mixture is cooled in an icebath and basified with solid potassium carbonate. The solution isextracted three times with ethyl acetate and the combined organic phasesare washed with saturated aqueous sodium chloride then dried overanhydrous sodium sulfate. Concentration under reduced pressure andrecrystallization from hexanes provides the desired product as a paleyellow crystalline solid.

[0541] Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

[0542] 5-Bromo-pyridin-3-ylamine

[0543] 3-Chloro-4-methanesulfonyl-phenylamine

[0544] N-(4-Amino-phenyl)-2-methyl-benzamide

[0545] Acetic acid 2-(4-amino-phenylcarbamoyl)-phenyl ester

[0546] N-(4-Amino-phenyl)-4-fluoro-benzamide

[0547] N-(4-Amino-phenyl)-3-fluoro-benzamide

[0548] N-(4-Amino-phenyl)-2-fluoro-benzamide

[0549] N-(4-Amino-phenyl)-2-methoxy-benzamide

[0550] N-(4-Amino-phenyl)-3-methoxy-benzamide

[0551] N-(4-Amino-phenyl)-4-methoxy-benzamide

[0552] N-(4-Amino-phenyl)-2-phenyl-acetamide

[0553] N-(4-Amino-phenyl)-2,2-dimethyl-propionamide

[0554] N-(4-Amino-phenyl)-2,2,2-trifluoro-acetamide

[0555] Thiophene-2-carboxylic acid (4-amino-phenyl)-amide

[0556] 1H-Pyrrole-2-carboxylic acid (4-amino-phenyl)-amide

[0557] N-(4-Amino-phenyl)-3-nitro-benzamide

[0558] 3-Acetylamino-N-(4-amino-phenyl)-benzamide

[0559] N-(4-Amino-phenyl)-3-dimethylamino-benzamide

[0560] N-(4-Amino-phenyl)-3-methanesulfonylamino-benzamide

[0561] N-(4-Amino-phenyl)-2-trifluoromethyl-benzamide

[0562] N-(4-Amino-phenyl)-2,6-difluoro-benzamide

[0563] N-(4-Amino-phenyl)-2-chloro-benzamide

[0564] N-(4-Amino-phenyl)-2-bromo-benzamide

[0565] N-(4-Amino-phenyl)-2-nitro-benzamide

[0566] Pyrazine-2-carboxylic acid (4-amino-phenyl)-amide

[0567] 5-Methyl-thiophene-2-carboxylic acid (4-amino-phenyl)-amide

[0568] Quinoline-8-carboxylic acid (4-amino-phenyl)-amide

[0569] 1-Methyl-1H-pyrrole-2-carboxylic acid (4-amino-phenyl)-amide

[0570] Benzo[b]thiophene-2-carboxylic acid (4-amino-phenyl)-amide

[0571] Benzofuran-2-carboxylic acid (4-amino-phenyl)-amide

[0572] N-(4-Amino-phenyl)-isonicotinamide

[0573] Naphthalene-2-carboxylic acid (4-amino-phenyl)-amide

[0574] Naphthalene-1-carboxylic acid (4-amino-phenyl)-amide

[0575] Isoquinoline-1-carboxylic acid (4-amino-phenyl)-amide

[0576] Quinoline-2-carboxylic acid (4-amino-phenyl)-amide

[0577] 3,5-Dichloro-4-ethoxy-phenylamine

[0578] 4-Butoxy-3,5-dichloro-phenylamine

[0579] Isoquinoline-4-carboxylic acid (4-amino-phenyl)-amide

[0580] [1,2,3]Thiadiazole-4-carboxylic acid (4-amino-phenyl)-amide

[0581] 1H-[1,2,3]Triazole-4-carboxylic acid (4-amino-phenyl)-amide

[0582] 3-Bromo-thiophene-2-carboxylic acid (4-amino-phenyl)-amide

[0583] 4-Benzyloxy-3,5-dichloro-phenylamine

[0584] 2-(4-Amino-2,6-dichloro-phenoxy)-acetamide

[0585] (4-Amino-2,6-dichloro-phenoxy)-acetic acid methyl ester

[0586] [3-(4-Amino-phenylcarbamoyl)-phenyl]-carbamic acid ethyl ester

[0587] 2-Amino-N-(4-amino-phenyl)-benzamide

[0588] Biphenyl-2-carboxylic acid (4-amino-phenyl)-amide

[0589] N-(4-Amino-phenyl)-2,3-difluoro-benzamide

[0590] N-(4-Amino-phenyl)-2,5-difluoro-benzamide

[0591] N-(4-Amino-phenyl)-2,4-difluoro-benzamide

[0592] 2-Acetylamino-N-(4-amino-phenyl)-benzamide

[0593] N-(4-Amino-phenyl)-2-methanesulfonylamino-benzamide

[0594] N-(4-Amino-phenyl)-2,3,4-trifluoro-benzamide

[0595] N-(4-Amino-phenyl)-2,3,4,5,6-pentafluoro-benzamide

[0596] N-(4-Amino-phenyl)-2-methylsulfanyl-benzamide

[0597] Acetic acid 2-(4-amino-2,6-dichloro-phenoxy)-ethyl ester

[0598] N-(4-Amino-phenyl)-isophthalamic acid methyl ester

[0599] N-(4-Amino-phenyl)-3-benzyloxy-benzamide

[0600] N-(4-Amino-phenyl)-3-butoxy-benzamide

[0601] [3-(4-Amino-phenylcarbamoyl)-phenoxy]-acetic acid ethyl ester

[0602] Pyridine-2-carboxylic acid (4-amino-phenyl)-amide

[0603] Quinoline-4-carboxylic acid (4-amino-phenyl)-amide

[0604] 5-Methyl-furan-2-carboxylic acid (4-amino-phenyl)-amide

[0605] 5-Difluoromethyl-furan-2-carboxylic acid (4-amino-phenyl)-amide

[0606] 1H-Indole-2-carboxylic acid (4-amino-phenyl)-amide

[0607] 4-Methyl-[1,2,3]thiadiazole-5-carboxylic acid(4-amino-phenyl)-amide

[0608] Thiophene-3-carboxylic acid (4-amino-phenyl)-amide

[0609] 5-Chloro-furan-2-carboxylic acid (4-amino-phenyl)-amide

[0610] 5-Nitro-furan-2-carboxylic acid (4-amino-phenyl)-amide

[0611] N-(4-Amino-phenyl)-2-thiophen-2-yl-acetamide

[0612] 3-Methyl-furan-2-carboxylic acid (4-amino-phenyl)-amide

[0613] 5-Bromo-furan-2-carboxylic acid (4-amino-phenyl)-amide

[0614] 4-Bromo-furan-2-carboxylic acid (4-amino-phenyl)-amide

[0615] N-(4-Amino-phenyl)-nicotinamide

[0616] N-(4-Aminophenyl)-3-furancarboxamide

[0617] 4-Phenyl-[1,2,3]thiadiazole-5-carboxylic acid(4-amino-phenyl)-amide

[0618] Acetic acid 3-(4-amino-phenylcarbamoyl)-phenyl ester

[0619] Benzo[1,3]dioxole-4-carboxylic acid (4-amino-phenyl)-amide

[0620] N-(4-Amino-phenyl)-3-(2-dimethylamino-ethoxy)-benzamide

[0621] N-(4-Amino-phenyl)-3-trifluoromethoxy-benzamide

[0622] N-(4-Amino-phenyl)-3-(2-morpholin-4-yl-ethoxy)-benzamide

[0623] (4-Amino-phenyl)-carbamic acid hexyl ester

[0624] Furan-2-carboxylic acid (4-amino-phenyl)-amide

[0625] (4-Amino-phenyl)-carbamic acid phenyl ester

[0626] Hexanoic acid (4-amino-phenyl)-amide

[0627] N-(4-Amino-phenyl)-acrylamide

[0628] N-(4-Amino-phenyl)-2-methoxy-acetamide

[0629] 4-Furan-3-yl-[1,2,3]thiadiazole-5-carboxylic acid(4-amino-phenyl)-amide

[0630] 5-tert-Butyl-furan-2-carboxylic acid (4-amino-phenyl)-amide

[0631] 3-Chloro-4-methanesulfinyl-phenylamine

[0632] 5-Methyl-[1,2,3]thiadiazole-4-carboxylic acid(4-amino-phenyl)-amide

[0633] 2-(4-Amino-2-chloro-phenyl)-ethanol

[0634] (4-Amino-2-chloro-phenyl)-carbamic acid 2-piperidin-1-yl-ethylester

[0635] 5-Chloro-N,N-dimethyl-benzene-1,3-diamine

[0636] 3-(2-Methyl-butyl)-5-trifluoromethyl-phenylamine

[0637] 3-Isobutyl-5-trifluoromethyl-phenylamine

[0638] Furan-2-carboxylic acid (4-aminomethyl-phenyl)-amide

[0639] N-(4-Aminomethyl-phenyl)-2-fluoro-benzamide

[0640] [1,2,3]Thiadiazole-4-carboxylic acid (4-aminomethyl-phenyl)-amide

[0641] N-(4-Aminomethyl-phenyl)-2,6-difluoro-benzamide

[0642] Oxazole-4-carboxylic acid (4-amino-phenyl)-amide

[0643] N-(4-Amino-phenyl)-3-chloro-benzamide

[0644] N-(4-Amino-phenyl)-4-chloro-benzamide

[0645] Acetic acid 4-(4-amino-phenylcarbamoyl)-phenyl ester

[0646] N-(4-Amino-phenyl)-4-dimethylamino-benzamide

[0647] 1-(4-Amino-phenyl)-3-(3,5-bis-trifluoromethyl-phenyl)-thiourea

[0648] N-(4-Amino-phenyl)-2-iodo-benzamide

[0649] N-(4-Amino-phenyl)-3-trifluoromethyl-benzamide

EXAMPLE 16 (METHOD 3B) 1-(4-Amino-2-chloro-phenyl)-ethanol

[0650] A 1M solution of tetrabutylammonium fluoride in tetrahydrofuran(5.7 mL) is added to [3-chloro-4-(1-hydroxy-ethyl)-phenyl]-carbamic acid2-trimethylsilanyl-ethyl ester (0.5 g) and the mixture is stirred atroom temperature for approximately 3.5 hours. The solution is thenconcentrated under reduced pressure, dissolved in a 1:1 mixture of ethylacetate and hexanes, washed successively with water then saturatedaqueous sodium chloride, and dried over anhydrous magnesium sulfate.Removal of the solvent under reduced pressure followed by chromatographyover silica gel (40% ethyl acetate in hexanes is used as the eluant)provides the product as an amber oil.

EXAMPLE 17 (METHOD 3C) N-(4-Amino-3-cyanophenyl)-2-fluoro-benzamide

[0651] Potassium carbonate (5.0 g) is added to a solution ofN-[3-cyano-4-(2,2,2-trifluoroacetyl-amino)-phenyl]-2-fluoro-benzamide(2.5 g) in methanol (270 mL) and water (16 mL) and the mixture isrefluxed overnight. After removing the solvent under reduced pressure,the residue is suspended in water and extracted with dichloromethane.The organic extracts are pooled, washed with water and then saturatedaqueous sodium chloride, dried over anhydrous magnesium sulfate,filtered and concentrated under reduced pressure to provide the desiredcompound as a white solid.

[0652] Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

[0653] N-(4-Amino-phenyl)-2-methanesulfinyl-benzamide

[0654] N-(4-Amino-3-cyano-phenyl)-2-fluoro-benzamide

[0655] Furan-2-carboxylic acid (4-amino-3-cyano-phenyl)-amide

[0656] N-(4-Amino-3-cyano-phenyl)-acetamide

[0657] Furan-2-carboxylic acid (4-amino-3-trifluoromethyl-phenyl)-amide

[0658] N-(4-Amino-3-methoxy-phenyl)-acetamide

[0659] N-(4-Amino-3-methoxy-phenyl)-2-fluoro-benzamide

[0660] Furan-2-carboxylic acid (4-amino-3-methoxy-phenyl)-amide

EXAMPLE 17 (METHOD 4A) 2-Chloro-1-cyclohexyloxy-4-nitro-benzene

[0661] Cylcohexanol (2.9 g) in dimethylsulfoxide (20 mL) is added slowlyto a flask containing potassium hydride (0.90 g, pre-washed three timeswith hexanes) under an atmosphere of argon and the solution is stirredfor about 1 hour at room temperature. A solution of3-chloro-4-fluoro-nitrobenzene (1 g) in dimethylsulfoxide (10 mL) isadded and the resulting dark red colored solution is then heated forthree hours to approximately 100 degrees. The reaction mixture is thencooled, diluted with diethyl ether (300 mL), and washed successivelywith saturated aqueous ammonium chloride, three times with water, thenwith saturated aqueous sodium chloride. The organic layer is then driedover anhydrous magnesium sulfate, the solvent is removed under reducedpressure, and the resulting oil is chromatographed over silica gel (5%ethyl acetate in hexanes is used as the eluant) to provide the desiredproduct as an orange solid.

EXAMPLE 18 (METHOD 4C)(2-Chloro-4-nitro-phenyl)-methyl(1-methyl-pyrrolidin-3-yl)-amine

[0662] 3-Chloro-4-fluoronitrobenzene (1.0 g) andN,N′-dimethyl-3-aminopyrrolidine (1.72 g) are combined and stirred forapproximately 24 hours. The mixture is then diluted with ethyl acetate,washed twice with water and once with saturated sodium chloride, anddried over anhydrous sodium sulfate. After removal of the solvent underreduced pressure the residue is chromatographed over silica gel (pureethyl acetate followed by pure methanol is used as the eluants) toprovide the desired product as a yellow oil.

[0663] Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

[0664] (2-Chloro-4-nitro-phenyl)-dipropyl-amine

[0665] 1-(2-Chloro-4-nitro-phenyl)-piperidine

[0666] 1-(2-Chloro-4-nitro-phenyl)-pyrrolidine

[0667] (2-Chloro-4-nitro-phenyl)-cyclohexyl-methyl-amine

[0668] Benzyl-(2-chloro-4-nitro-phenyl)-amine

[0669] (2-Chloro-4-nitro-phenyl)-methyl-(1-methyl-piperidin-4-yl)-amine

[0670] (2-Chloro-4-nitro-phenyl)-cyclohexyl-ethyl-amine

[0671] (2-Chloro-4-nitro-phenyl)-cyclohexyl-amine

[0672] (2-Chloro-4-nitro-phenyl)-methyl-(1-methyl-pyrrolidin-3-yl)-amine

[0673] (1-Benzyl-pyrrolidin-3-yl)-(2chloro-4-nitro-phenyl)-methyl-amine

[0674] (2-Chloro-4-nitro-phenyl)-cyclopentyl-methyl-amine

[0675] 1-(2-Chloro-4-nitro-phenyl)-decahydro-quinoline

[0676] Allyl-(2-chloro-4-nitro-phenyl)-cyclohexyl-amine

[0677] 2-[(2-Chloro-4-nitro-phenyl)-(2-hydroxy-ethyl)-amino]-ethanol

[0678] (2-Chloro-4-nitro-phenyl)-isobutyl-methyl-amine

[0679] (2-Chloro-4-nitro-phenyl)-hexyl-methyl-amine

[0680] 2-[(2-Chloro-4-nitro-phenyl)-methyl-amino]-ethanol

[0681] N-(2-Chloro-4-nitro-phenyl)-N,N′,N′-trimethyl-ethane-1,2-diamine

[0682] N-(2-Chloro-4-nitro-phenyl)-N,N′,N′-trimethyl-propane-1,3-diamine

[0683] (1-Benzyl-piperidin-4-yl)-(2-chloro-4-nitro-phenyl)-amine

[0684] N-(2-Chloro-4-nitro-phenyl)-N′,N′-dimethyl-ethane-1,2-diamine

[0685] N-(2-Chloro-4-nitro-phenyl)-N′,N′-dimethyl-propane-1,3-diamine

[0686] (2-Chloro-4-nitro-phenyl)-(2-methoxy-ethyl)-methyl-amine

[0687] (1-Benzyl-pyrrolidin-3-yl)-(2-chloro-4-nitro-phenyl)-amine

[0688] 4-Piperidin-1-yl-3-trifluoromethyl-benzonitrile

[0689] 4-Dimethylamino-3-trifluoromethyl-benzonitrile

[0690] 4-(4-Methyl-piperazin-1-yl)-3-trifluoromethyl-benzonitrile

EXAMPLE 19 (METHOD 4E) Butyl-(2-chloro-4-nitro-phenyl)thioether

[0691] A solution of 3-chloro-4-fluoro-nitrobenzene (5.0 g) and sodiumsulfide (2.5 g) in N,N-dimethylformamide (30 mL) is stirred at roomtemperature for 1 hour and then treated with 1-iodobutane (12.6 g). Thesolvent is then removed under reduced pressure and the resulting residueis treated with ethyl acetate and hexanes to precipitate the inorganicsalts. The solids are removed by filtration and the filtrate is reducedunder reduced pressure. The resulting residue is then passed throughhydrous magnesium silicate using dichloromethane as the eluent toprovide the desired compound as a yellow solid.

[0692] Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

[0693] 1-Butylsulfanyl-2-chloro-4-nitro-benzene

[0694] 2-Chloro-1-cyclohexylsulfanyl-4-nitro-benzene

[0695] 2-Chloro-1-ethylsulfanyl-4-nitro-benzene

EXAMPLE 20 (METHOD 4F)(4-Chloro-5-methoxy-2-nitro-phenyl)-dimethyl-amine

[0696] To a solution of trifluoro-methanesulfonic acid4-chloro-5-methoxy-2-nitro-phenyl ester (1.0 g) in tetrahydrofuran (2.0mL) is added dimethylamine (4.0 mL of a 40% aqueous solution) and themixture is stirred at room temperature for approximately 15 hours. Thesolution is then concentrated under reduced pressure and the residue isdissolved in ethyl acetate and then washed with water. The aqueous layeris extracted once with ethyl acetate and the combined organic layers arewashed with saturated aqueous sodium chloride and dried over anhydroussodium sulfate. The solvent is removed by evaporation under reducedpressure and the residue is triturated with hexanes to provide thedesired product as a colorless solid.

[0697] Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

[0698] (4-Chloro-2-nitro-phenyl)-dimethyl-amine

[0699] 4-(4-Chloro-5-methoxy-2-nitro-phenyl)-morpholine

[0700] (4-Chloro-5-methoxy-2-nitro-phenyl)-dimethyl-amine

[0701] 1-(4-Chloro-5-methoxy-2-nitro-phenyl)-piperidine

[0702] 1-(4-Chloro-5-methoxy-2-nitro-phenyl)-pyrrolidine

[0703] Benzyl-(4-chloro-5-methoxy-2-nitro-phenyl)-amine

[0704] (2-Chloro-6-nitro-phenyl)-dimethyl-amine

EXAMPLE 21 (METHOD 4G) (2-Chloro-4-nitro-phenyl)-methyl-phenyl-amine

[0705] n-Butyl lithium (12.3 mL of a 2.5 M solution in hexanes) is addeddropwise to a solution of N-methyl aniline (3.0 g) in tetrahydrofuran(75 mL) at 0° C. The mixture is allowed to warm slowly to roomtemperature and is then re-cooled to 0° C. and added by cannula to asolution of 3-chloro-4-fluoronitrobenzene (4.9 g) in tetrahydrofuran (35mL) that is kept at −78° C. Following the addition, the reaction mixtureis permitted to warm to room temperature over the course of 1 hour, andis then concentrated under reduced pressure, quenched by addition ofsaturated aqueous ammonium chloride, and extracted three times withethyl acetate. The pooled organic layers are washed three times with 5%aqueous hydrochloric acid, once with water, once with saturated aqueoussodium bicarbonate, once with saturated aqueous sodium chloride, andthen dried over anhydrous magnesium sulfate. Following removal of thesolvent under reduced pressure the residue is chromatographed oversilica gel (5% diethyl ether in hexanes is used as the eluant) toprovide the desired product as a clear colorless oil.

EXAMPLE 22 (METHOD 4H) 2,6-Dichloro-4-nitrophenol

[0706] 3,4,5-Trichloronitrobenzene (14.86 g) is added to a solution ofpotassium phenoxide (8.66 g) in diethylene glycol (66 mL) and themixture is heated to 160° C. for approximately 15 hours. The resultingdark brown solution is cooled to room temperature, poured onto 100 mLcold water, and extracted twice with diethyl ether. The pooled organicextracts are washed with water, 10% aqueous sodium hydroxide, and thendried over anhydrous magnesium sulfate. Following removal of the solventunder reduced pressure the resulting oil is distilled in a Kugelrohrapparatus to provide a yellow oil that solidifies on standing.Recrystallization from ethanol-water provides the desired product as apale yellow solid.

EXAMPLE 23 (METHOD 5A) (3,5-Dichloro-4-ethoxy-phenyl)-carbamic AcidTert-Butyl Ester

[0707] To a solution of (3,5-dichloro-4-hydroxy-phenyl)-carbamic acidtert-butyl ester (1.0 g) and potassium carbonate (1.0 g) in acetone (18mL) is added ethyl iodide (0.36 mL) and the mixture is stirred forapproximately 15 hours at room temperature. The solution is thenfiltered, concentrated under reduced pressure, and partitioned betweenethyl acetate and water. The separated aqueous layer is furtherextracted twice with ethyl acetate, and the pooled organic extracts arewashed successively with 10% aqueous sodium hydroxide, with water, andthen dried over anhydrous sodium sulfate. Evaporation of the solventunder reduced pressure gave the desired product as a tan solid.

[0708] Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

[0709] (3,5-Dichloro-4-ethoxy-phenyl)-carbamic acid tert-butyl ester

[0710] (4-Butoxy-3,5-dichloro-phenyl)-carbamic acid tert-butyl ester

[0711] (4-Benzyloxy-3,5-dichloro-phenyl)-carbamic acid tert-butyl ester

[0712] (4-Carbamoylmethoxy-3,5-dichloro-phenyl)-carbamic acid tert-butylester

[0713] [3,5-Dichloro-4-(2-nitrilo-ethoxy)-phenyl]-carbamic acidtert-butyl ester

[0714] (4-tert-Butoxycarbonylamino-2,6-dichloro-phenoxy)-acetic acidmethyl ester

[0715] 3-Butoxy-benzoic acid methyl ester

[0716] 3-tert-Butoxycarbonylmethoxy-benzoic acid methyl ester

[0717] 3-Carbamoylmethoxy-benzoic acid methyl ester

[0718] [4-(3-Carbamoylmethoxy-benzoylamino)-phenyl]-carbamic acidtert-butyl ester

[0719] (4-[3-(2-Chloro-ethoxy)-benzoylamino]-phenyl)-carbamic acidtert-butyl ester

EXAMPLE 24 (METHOD 5C) (2,6-Dichloro-4-nitro-phenoxy)-acetic acidtert-butyl ester

[0720] To a solution of 2,6-dichloro-4-nitrophenol (2.5 g) and potassiumcarbonate (3.3 g) in dimethyl-formamide (50 mL) is addedtert-butyl-bromoacetate (10 mL) and the mixture is stirred at roomtemperature for two days. The solution is then poured into 500 mL water,extracted three times with hexanes, and the pooled organic extracts arewashed with saturated aqueous ammonium chloride and then dried overanhydrous magnesium sulfate. Evaporation of the solvent under reducedpressure followed by trituration of the resulting oil with hexanesprovides the desired product as a white solid.

[0721] Using the above procedure and starting materials the followingcompounds were prepared:

[0722] 3-Dimethylamino-1-(4-nitro-phenyl)-propenone

[0723] 2-Chloro-1-isopropoxy-4-nitro-benzene

[0724] 1,3-Dichloro-2-methoxy-4-methyl-5-nitro-benzene

[0725] 1-Chloro-4-ethoxy-2-methoxy-5-nitro-benzene

[0726] 1-Butoxy-4-chloro-5-methoxy-2-nitro-benzene

[0727] 1-Chloro-2-methoxy-5-nitro-4-(phenylmethoxy)benzene (CA name)

[0728] 1-Chloro-4-methoxy-5-nitro-2-(phenylmethoxy)benzene (CA name)

[0729] (2,6-Dichloro-4-nitro-phenoxy)-acetic acid tert-butyl ester

[0730] (2,6-Dichloro-4-nitro-phenoxy)-acetonitrile

[0731] 1-Chloro-4-methoxy-2-methyl-5-nitro-benzene

[0732] 2-(4-Chloro-5-methoxy-2-nitro-phenoxy)-acetamide

[0733] 2-(2-Chloro-5-methoxy-4-nitro-phenoxy)-acetamide

[0734] (4-Chloro-5-methoxy-2-nitro-phenoxy)-acetonitrile

[0735] (2-Chloro-5-methoxy-4-nitro-phenoxy)-acetonitrile

[0736] 4-(2-Chloro-5-methoxy-4-nitro-phenoxy)-butyronitrile

[0737] 2-(4-Chloro-5-methoxy-2-nitro-phenoxy)-ethanol

[0738] 2-(2-Chloro-5-methoxy-4-nitro-phenoxy)-ethanol

[0739] (2-Chloro-5-methoxy-4-nitro-phenoxy)-acetic acid tert-butyl ester

[0740] (2-Chloro-5-methoxy-4-nitro-phenoxy)-acetic acid methyl ester

[0741] (4-Chloro-5-methoxy-2-nitro-phenoxy)-acetic acid methyl ester

[0742] (4-Chloro-5-methoxy-2-nitro-phenoxy)-acetic acid tert-butyl ester

[0743] (2-Chloro-4-nitro-phenoxy)-acetonitrile

[0744] 1-Butoxy-2-chloro-4-nitro-benzene

[0745] 2-Chloro-4-nitro-1-(2,2,2-trifluoro-ethoxy)-benzene

[0746] 2-Chloro-4-nitro-1-propoxy-benzene

[0747] 2-Chloro-1-ethoxy-4-nitro-benzene

[0748] 1,3-Diiodo-2,4-dimethoxy-5-nitro-benzene

[0749] 1,3-Dibromo-2,4-dimethoxy-5-nitro-benzene

[0750] 3-Chloro-2,4-dimethoxy-nitrobenzene

EXAMPLE 25 (METHOD 5E)[3,5-Dichloro-4-(2-hydroxy-ethoxy)-phenyl]-carbamic Acid Tert-ButylEster

[0751] To a solution of (3,5-dichloro-4-hydroxy-phenyl)-carbamic acidtert-butyl ester (1.0 g) and potassium carbonate (0.55 g) in toluene (20mL) is added ethylene carbonate (1.6 g) and the mixture is heatedtoreflux for 3 hours. To the cooled reaction mixture is added 2.5 Maqueous sodium hydroxide (50 mL), and the separated organic layer isthen washed successively with water, then saturated aqueous sodiumchloride, and then dried over anhydrous sodium sulfate. The solvent isthen removed by evaporation under reduced pressure and the resultingresidue is chromatographed over silica gel (30% ethyl acetate in hexanesis used as the eluant) to provide the desired product as a white foam.

EXAMPLE 26 (METHOD 6) 3-(2-Chloro-4-nitro-phenoxy)-1-methyl-pyrrolidine

[0752] To a solution of 2-chloro-4-nitrophenol (2.0 g) intetrahydrofuran (60 mL) is added 1-methyl-3-pyrrolidinol (2.3 g),triphenyl phosphine (6.0 g), and diethylazodicarboxylate (3.6 mL) andthe mixture is stirred at room temperature under an atmosphere of argonfor 1.5 hours. The solution is then concentrated under reduced pressure,diluted with ethyl acetate, washed successively with 10% aqueous sodiumhydroxide, water, saturated aqueous sodium chloride, and dried overanhydrous magnesium sulfate. The solvent is removed by evaporation underreduced pressure and the residue is chromatographed over silica gel(ethyl acetate then 10% methanol in dichloromethane is used as theeluant). Pooled product fractions are then recrystallized from hexanesto provide the desired product as a yellow solid.

[0753] Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

[0754] 4-(2-Chloro-4-nitro-phenoxy)-1-methyl-piperidine

[0755] 3-(2-Chloro-4-nitro-phenoxy)-1-methyl-pyrrolidine

[0756] [2-(2-Chloro-4-nitro-phenoxy)-ethyl]-dimethyl-amine

[0757] [3-(2-Chloro-4-nitro-phenoxy)-propyl]-dimethyl-amine

EXAMPLE 27 (METHOD 7A) 2-Chloro-3-methoxy-6-nitro-phenol and2,4-Dichloro-3-methoxy-6-nitro-phenol

[0758] To a flask containing 3-methoxy-6-nitro-phenol (0.5 g) is addedaqueous sodium hypochlorite (5.25% aqueous solution, 21 mL) and themixture is stirred at room temperature for approximately 24 hours. Themixture is then cooled in an ice-bath, acidified by addition ofconcentrated hydrochloric acid, then extracted twice with ethyl acetate.These organic extracts are dried over anhydrous magnesium sulfate, thesolvent is removed by evaporation under reduced pressure, and theresidue is chromatographed over silca gel (15% acetone in hexanes isused as the eluant) to provide both the mono- and di-chlorinatedproducts as yellow solids.

[0759] Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

[0760] 3-Chloro-2-hydroxy-4-methoxy-nitrobenzene

[0761] 3,5-Dichloro-2-hydroxy-4-methoxy-nitrobenzene

EXAMPLE 28 (METHOD 7B) 2,4-Dichloro-3-methyl-6-nitro-phenol

[0762] To a solution of 3-methyl-4-nitro-phenol (5.0 g) in water (150mL) is added aqueous sodium hypochlorite (5.25% aqueous solution, 230mL) and the mixture is stirred at room temperature for approximately 15hours. Additional aqueous sodium hypochlorite (5.25% aqueous solution,230 mL) is added and the mixture is permitted to stir at roomtemperature for 2.5 days. The mixture is then cooled in an ice-bath,acidified by addition of concentrated hydrochloric acid, then extractedtwice with ethyl acetate. These organic extracts are dried overanhydrous magnesium sulfate, the solvent is removed by evaporation underreduced pressure, and the residue is chromatographed over silca gel(ethyl acetate is used as the eluant) to provide the desired product asa yellow solid. An analytically pure sample is obtained by a singlerecrystallization from chloroform.

EXAMPLE 29 (METHOD 7C) 1-Bromo-2,4-dimethoxy-5-nitro-benzene

[0763] To a solution of 2,4-dimethoxy-nitrobenzene (0.50 g) inchloroform (3 mL) is added dropwise a solution of bromine (0.23 g) inchloroform (1 mL) and the mixture is allowed to stir at room temperaturefor approximately 15 hours. Additional bromine (0.15 g) in chloroform (1mL) is added and the reaction is stirred for an additional 4 hours. Themixture is then poured onto 5% aqueous sodium bisulfite and thenextracted with chloroform. Pooled organic extracts are then washedsuccessively with 5% aqueous sodium bisulfite then saturated sodiumchloride, and then dried over anhydrous sodium sulfate. Removal of thesolvent under reduced pressure and recrystallization of the residue fromtoluene provides the desired product as a yellow solid.

EXAMPLE 30 (METHOD 7D) 2,4-Dibromo-3-methoxy-6-nitro-phenol

[0764] To a solution of 5-methoxy-2-nitro-phenol (0.25 g) and silvertrifluoroacetate (0.49 g) in glacial acetic acid (3 mL) is addeddropwise a solution of bromine (1.42 g) in glacial acetic acid (3 mL)and the mixture is stirred at room temperature for approximately 24hours. The solution is then partitioned between ethyl acetate and water,and the organic layer is washed successively three times with 5% aqueoussodium bisulfite, three times with saturated aqueous sodium bicarbonate,and once with saturated aqueous sodium chloride. The organic layer isthen dried over anhydrous magnesium sulfate and the solvent is removedunder reduced pressure. The residue is chromatographed over silica gel(20% ethyl acetate in hexanes is used as the eluant) then recrystallizedfrom chloroform to provide the desired dibrominated product as an orangesolid.

EXAMPLE 31 (METHOD 7E) 1-Iodo-2,4-dimethoxy-5-nitro-benzene

[0765] To a solution of 2,4-dimethoxy-nitrobenzene (1.0 g) in glacialacetic acid (30 mL) is added benzyltrimethylammonium dichloroiodate(1.90 g) and anhydrous zinc chloride (1.0 g) and the mixture is stirredat room temperature under an atmosphere of argon. Additionalbenzyltrimethylammonium dichloroiodate (0.4 g) is added after 5 hoursand again after 24 hours. Additional zinc chloride (0.5 g) and glacialacetic acid (15 mL) is added after 24 hours. The mixture is permitted tostir at room temperature for 3 days and is then filtered, diluted with5% aqueous sodium bisulfite, and extracted three times with ethylacetate. These pooled organic extracts are washed successively with 5%aqueous sodium bisulfite, saturated aqueous sodium chloride, then driedover anhydrous magnesium sulfate. After removal of the solvent underreduced pressure the residue is triturated with hexanes to provide thedesired product as a pale yellow solid.

EXAMPLE 32 (METHOD 7F) 2,4-Diiodo-3-methoxy-6-nitro-phenol

[0766] To a solution of 5-methoxy-2-nitro-phenol (0.25 g) indichloromethane (15 mL) and methanol (6 mL) is addedbenzyltrimethylammonium dichloroiodate (1.08 g) and sodium bicarbonate(0.85 g) and the mixture is allowed to stir at room temperature for 24hours. The solution is then filtered, the filtrate is concentrated underreduced pressure, the residue is dissolved in ethyl acetate and thenwashed successively with 5% aqueous sodium bicarbonate, 5% aqueoussodium bisulfite, and saturated aqueous sodium chloride. After dryingover anhydrous magnesium sulfate the solvent is removed by evaporationunder reduced pressure and the residue is recrystallized from toluene toprovide the desired product as yellow needles.

EXAMPLE 33 (METHOD 7G) 1-Fluoro-2,4-dimethoxy-5-nitro-benzene

[0767] To a solution of 2,4-dimethoxy-nitrobenzene (1.0 g) intetrachloroethane (10 mL) is added 3,5-dichloro-l-fluoro-pyridiniumtriflate (85%, 5.07 g) and the mixture is heated to 120° C. for 5 hours.Additional 3,5-dichloro-l-fluoro-pyridinium triflate (85%, 0.25 g) isadded and heating is continued for 1 hour. The solution is then cooledto room temperature and passed over a column of silica gel (hexanesfollowed by 30% ethyl acetate in hexanes is used as the eluant). Productcontaining fractions are combined, evaporated under reduced pressure,and the residue is crystallized from hexanes to provide the desiredproduct as a tan solid.

EXAMPLE 34 (METHOD 8) 3-Chloro-4-trifluoromethyl-nitrobenzene

[0768] A solution of 3-chloro-4-iodo-nitrobenzene (2.26 g),trimethyl(trifluoromethyl)silane (5.68 g), copper(I) iodide (2.28 g),and potassium fluoride (0.56 g) in N,N-dimethylformamide (8 mL) isheated in a sealed tube to 80° C. for 40 hours. The solution is thencooled, diluted with diethyl ether, filtered through diatomaceous earth,and the filtrate is washed successively with water, saturated aqueoussodium chloride, and then dried over anhydrous sodium sulfate. Thesolvent is removed under reduced pressure and the residue ischromatographed over silica gel (1% diethyl ether in hexanes followed by10% ethyl acetate in hexanes is used as the eluant) to provided thedesired product as a colorless oil.

EXAMPLE 35 (METHOD 9) (3-Chloro-4-methanesulfinyl-phenyl)-carbamic AcidTert-Butyl Ester

[0769] To a solution of (3-chloro-4-thiomethyl-phenyl)-carbamic acidtert-butyl ester (0.89 g) in dichloromethane (15 mL) at 0° C. is added asolution of dimethyldioxirane (˜0.11 M in acetone, 34 mL) and themixture is stirred at 0° C. for 1 hour. The solvent is removed underreduced pressure and the residue is dissolved in dichloromethane, washedwith saturated aqueous sodium chloride, and then dried over anhydrousmagnesium sulfate. Removal of the solvent under reduced pressure gavethe desired product as an orange foam.

EXAMPLE 36 (METHOD 9B)[4-(2-Methylsulfinyl-benzoylamino)-phenyl]-carbamic Acid Tert-ButylEster

[0770] To a solution of2-methylsulfanyl-N-[4-(2,2,2-trifluoro-acetylamino)-phenyl]-benzamide(234 mg) is added a saturated solution of sodium periodate (5 mL) andthe mixture is stirred for 12 hours. The purple mixture is poured intowater, extracted with ethyl acetate, dried over anhydrous potassiumcarbonate and evaporated to yield a red solid, 101 mg.

[0771] Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

[0772] [4-(2-Methanesulfinyl-benzoylamino)-phenyl]-carbamic acidtert-butyl ester

[0773]2-Methanesulfinyl-N-[4-(2,2,2-trifluoro-acetylamino)-phenyl]-benzamide

EXAMPLE 37 (METHOD 10) (3-Chloro-4-methanesulfonyl-phenyl)-carbamic AcidTert-Butyl Ester

[0774] To a solution of (3-chloro-4-thiomethyl-phenyl)-carbamic acidtert-butyl ester (0.90 g) in dichloromethane (30 mL) at 0° C. is added asolution of dimethyldioxirane (0.11 M in acetone, 80 mL) and the mixtureis stirred at 0° C. for 1 hour. The solvent is removed under reducedpressure and the residue is dissolved in dichloromethane, washed withsaturated aqueous sodium chloride, and then dried over anhydrousmagnesium sulfate. Removal of the solvent under reduced pressure givesthe desired product as an orange foam.

EXAMPLE 38 (METHOD 11) 3-Chloro-4-vinyl-phenylamine

[0775] To a deoxygenated solution of 3-chloro-4-iodo-aniline (6.95 g),triphenyl arsine (0.67 g), and tris(dibenzylideneacetone)palladium(0)(0.50,g) in tetrahydrofuran (120 mL) at 50° C. is added tributylvinyltin(10 g) and the mixture is stirred for approximately 15 hours at 50° C.under an atmosphere of argon. The reaction is then cooled, filteredthrough diatomaceous earth, and the filtrate is evaporated to drynessunder reduced pressure. The residue is dissolved in hexanes and thenextracted three times with 5% aqueous hydrochloric acid. These aqueousacidic extracts are then basified with solid potassium carbonate andextracted three times with ethyl acetate. These pooled organic extractsare then washed with saturated aqueous sodium chloride, dried over.anhydrous magnesium sulfate, and the solvent is removed under reducedpressure. The resulting residue is chromatographed over silica gel(hexanes and then 10% ethyl acetate in hexanes is used as the eluant) toprovide the desired product as an amber oil.

EXAMPLE 39 (METHOD 12) [3-Chloro-4-(1-hydroxy-ethyl)-phenyl]-carbamicacid 2-trimethylsilanyl-ethyl ester

[0776] (3-Chloro-4-vinyl-phenyl)-carbamic acid 2-trimethylsilanyl-ethylester (2.6 g) is added to a solution of mercuric acetate (3.48 g) inwater (7 mL) and tetrahydrofuran (5.25 mL) and the mixture is stirredfor approximately 15 hours. 3N Aqueous sodium hydroxide (8.7 mL) and a0.5 M solution of sodium borohydride in 3N aqueous sodium hydroxide (8.7mL) are then added and stirring is continued for 6 hours. The solutionis then saturated with sodium chloride and extracted with ethyl acetate.These organic extracts are then washed with saturated aqueous sodiumchloride and dried over anhydrous sodium sulfate. Following removal ofthe solvent under reduced pressure the residue is chromatographed oversilica gel (20% ethyl acetate in hexanes is used as the eluant) toprovide the desired product as a white solid.

EXAMPLE 40 (METHOD 13) [3-Chloro-4-(2-hydroxy-ethyl)-phenyl]-carbamicAcid Tert-Butyl Ester

[0777] To a stirring suspension of sodium borohydride (0.45 g) intetrahydrofuran (13 mL) at 0° C. is added glacial acetic acid (0.75 mL)and the mixture is stirred at 0° C. for 1 hour. The solution is thenwarmed to room temperature and (3-chloro-4-vinyl-phenyl)-carbamic acid2-trimethylsilanyl-ethyl ester (1.0 g) is added. The reaction is stirredat room temperature for approximately 15 hours and then heated to refluxfor approximately 20 hours. The mixture is then cooled and solutions of5 N aqueous sodium hydroxide (0.80 mL) and 30% aqueous hydrogen peroxide(0.56 mL) are added. After stirring for an additional 15 hours thelayers are separated, the aqueous layer is extracted three times withdiethyl ether, and these organic extracts are dried over anhydrousmagnesium sulfate. Following removal of the solvent under reducedpressure the residue is chromatographed over silica gel (40% ethylacetate in hexanes is used as the eluant) to provide the desired productas an amber oil.

EXAMPLE 41 (METHOD 14) [4-(1-Azido-ethyl)-3-chloro-phenyl]-carbamic Acid2-Trimethylsilanyl-Ethyl Ester

[0778] To a solution of [3-chloro-4-(1-hydroxy-ethyl)-phenyl]-carbamicacid 2-trimethylsilanyl-ethyl ester (1.25 g) in tetrahydrofuran (20 mL)at 0° C. under an atmosphere of argon is added triphenyl-phosphine (2.6g), hydrazoic acid (approximately 2.5 molar equivalents indichloromethane, prepared by the method of Fieser and Fieser, Reagentsfor Organic Synthesis, Vol. 1, pg. 446; Wiley, N.Y.) and diethylazodicarboxylate (1.72 g). After approximately 10 minutes the solvent isremoved under reduced pressure and the residue is chromatographed oversilica gel (5% ethyl acetate in hexanes is used as the eluant) toprovide the desired product as a colorless oil.

EXAMPLE 42 (METHOD 15)[3-Chloro-4-(3-dimethylamino-prop-1-ynyl)-phenyl]-carbamic AcidTert-Butyl Ester

[0779] To a deoxygenated solution of (3-chloro-4-iodo-phenyl)-carbamicacid tert-butyl ester (10.0 g) in triethylamine (120 ml) is addedl-dimethylamino-2-propyne (2.82 g),bis(triphenyl-phosphine)palladium(II) chloride (0.4 g), and cuprousiodide (0.054 g). The mixture is stirred at room temperature under anatmosphere of argon for approximately 6 hours and is then heated briefly(ca. 10 minutes) to 60° C. The reaction mixture is then cooled, filteredthrough diatomaceous earth, and the solvent is removed by evaporationunder reduced pressure. The residue is dissolved in ethyl acetate,washed three times with water, once with saturated aqueous sodiumchloride, and dried over anhydrous magnesium sulfate. The solvent isremoved by evaporation under reduced pressure, and the residue ischromatographed over silica gel (80% ethyl acetate in hexanes is used asthe eluant) to give the purified product as an amber oil that solidifiedon standing.

[0780] Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

[0781] [3-Chloro-4-(3-dimethylamino-prop-1-ynyl)-phenyl]-carbamic acidtert-butyl ester

[0782] [3-(4-Methoxy-phenyl)-prop-2-ynyl]-dimethyl-amine

[0783] 4-(3-Dimethylamino-prop-1-ynyl)-benzonitrile

[0784] Dimethyl-[3-(4-nitro-phenyl)-prop-2-ynyl]-amine

EXAMPLE 43 (METHOD 16)[3-Chloro-4-(3-dimethylamino-acryloyl)-phenyl]-carbamic Acid Tert-ButylEster

[0785] To an ice cold solution of[3-chloro-4-(3-dimethylamino-prop-1-ynyl)-phenyl]-carbamic acidtert-butyl ester (4.0 g) in dichloromethane (30 ml) is added in smallportions 3-chloroperoxybenzoic acid (2.34 g). After the reaction isstirred at 0° C. for 20 minutes, the mixture is passed over twentyweight equivalents of basic alumina (Brockmann Grade I, 150 mesh) andthe N-oxide is cluted using a solution of 5% methanol indichloromethane. All fractions containing the desired amine N-oxide werecombined and evaporated to near dryness under reduced pressure. Theresidue is treated successively three times with small portions ofmethanol (ca. 50 ml) followed by evaporation to near dryness underreduced pressure, and the volume of the solution is adjusted to 250 mLby addition of methanol. The methanolic solution of the N-oxide is thenheated to reflux for approximately 15 hours, then cooled, and thesolvent is evaporated to dryness under reduced pressure. The residue ispurified by chromatography over silica gel (80% ethyl acetate in hexanesis used as the eluant) to give the desired product as a pale yellowsolid.

EXAMPLE 44 (METHOD 17) (3-Chloro-4-isoxazol-5-yl-phenyl)-carbarnic AcidTert-Butyl Ester

[0786] A solution of[3-chloro-4-(3-dimethylamino-acryloyl)-phenyl]-carbamic acid tert-butylester (270 mg) in dioxane (3 ml) is treated with hydroxylaminehydrochloride (122 mg) and the mixture is stirred at room temperaturefor 10 days. The mixture is diluted with ethyl acetate, washedsuccessively with water, 5% aqueous sodium bicarbonate, saturatedaqueous sodium chloride, and then dried over anhydrous magnesiumsulfate. The solvent is removed by evaporation under reduced pressureand the resulting residue is chromatographed over silica gel (33% ethylacetate in hexanes is used as the eluant) to provide the desired productas a colorless solid.

EXAMPLE 45 (METHOD 18) [3-Chloro-4-(1H-pyrazol-3-yl)-phenyl]-carbamicAcid Tert-Butyl Ester

[0787] A solution of[3-chloro-4-(3-dimethylamino-acryloyl)-phenyl]-carbamic acid tert-butylester (250 mg) in ethanol (1.25 ml) is treated with hydrazine hydrate(0.25 ml) and the mixture is stirred at room temperature for 3 hours.The mixture is then diluted with 30 mL of diethyl ether, washed threetimes with water, once with saturated aqueous sodium chloride, and driedover anhydrous magnesium sulfate. The solvent is removed by evaporationunder reduced pressure and the resulting residue is chromatographed oversilica gel (67% ethyl acetate in hexanes is used as the eluant) toprovide the desired product as an oil.

EXAMPLE 46 (METHOD 19A)N-(2-Chloro-4-nitrophenyl)-2-thiomorpholino-4-yl-acetamide

[0788] To a solution N-(chloroacetyl)-2-chloro-4-nitroaniline (3.80 g)in tetrahydrofuran (50 mL) is added thiomorpholine (10 mL) and thesolution allowed to stand for 1 hour. This reaction mixture is pouredinto water a pale yellow solid is collected and then recrystallized fromhot 2-propanol to give a pale yellow crystalline solid.

[0789] Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

[0790] (4-{2-[Bis-(2-hydroxy-ethyl)-amino]-acetylamino}-phenyl)-carbamicacid tert-butyl ester

[0791] [4-(2-Dimethylamino-acetylamino)-phenyl]-carbamic acid tert-butylester

[0792] {4-[3-(2-Dimethylamino-ethoxy), benzoylamino]-phenyl}-carbamicacid tert-butyl ester

[0793] {4-[3-(2-Morpholin-4-yl-ethoxy)-benzoylamino]-phenyl}-carbamicacid tert-butyl ester

[0794] N-(2-Chloro-4-nitro-phenyl)-2-dimethylamino-acetamide

[0795] N-(2-Chloro-4-nitro-phenyl)-2-piperidin-1-yl-acetamide

[0796] N-(2-Chloro-4-nitro-phenyl)-2-morpholin-4-yl-acetamide

[0797] N-(2-Chloro-4-nitro-phenyl)-2-dipropylamino-acetamide

[0798] N-(2-Chloro-4-nitro-phenyl)-2-thiomorpholin-4-yl-acetamide

[0799] N-(2-Chloro-4-nitro-phenyl)-2-diethylamino-acetamide

[0800] N-(2-Chloro-4-nitro-phenyl)-2-pyrrolidin-1-yl-acetamide

[0801] 2-Azepan-1-yl-N-(2-chloro-4-nitro-phenyl)-acetamide

[0802] N-(2-Chloro-4-nitro-phenyl)-2-(2-methyl-piperidin-1-yl)-acetamide

[0803] N-(2-Chloro-4-nitro-phenyl)-2-(3-methyl-piperidin-1-yl)-acetamide

[0804] N-(2-Chloro-4-nitro-phenyl)-2-(4-methyl-piperidin-1-yl)-acetamide

EXAMPLE 47 (METHOD 19B)N-(2-Chloro-4-nitrophenyl)-2-(2-dimethylaminoethylsulfanyl)acetamide

[0805] To a solution of N-(chloroacetyl)-2-chloro-4-nitroaniline (3.01g) in N,N-dimethylformamide (100 mL) is added powdered sodium carbonate(6.0 g) and 2-dimethylaminoethanethiol hydrochloride (6.0 g). Themixture is stirred for 1 hour at 25° C., poured into water and extractedinto ethyl acetate. The ethyl acetate solution is dried over anhydrouspotassium carbonate and concentrated under reduced pressure to give anoil. The oil is crystallized from toluene-hexanes (3:1) to yield a paleyellow crystalline solid.

EXAMPLE 48 (METHOD 20)(4-tert-butoxycarbonylamino-2-chloro-phenyl)-carbamic Acid2-piperidin-1-yl-ethyl Ester

[0806] To a suspension of 1,1-carbonyl-di-(1,2,4)-triazole (4.0 g) indichloromethane (40 mL) is added a solution of (4-amino-3-chloro-phenyl)carbamic acid tert-butyl ester (5.0 g) in dichloromethane (45 mL)dropwise over 20 minutes. The reaction is stirred at room temperaturefor 30 minutes at which point a precipitate forms. To this mixture isadded piperidineethanol (6.6 mL) and tetra-hydrofuran (20 mL) is addedto maintain homogeneity. After heating at reflux overnight the reactionis cooled and then poured into water, the organic layer separated andthen washed with saturated aqueous sodium chloride. The solution isdried over anhydrous sodium sulfate, filtered and concentrated underreduced pressure to a crude oil that is purified by chromatography oversilica gel (5% methanol in dichloromethane is used as the eluant) togive the desired product as a white foam.

EXAMPLE 49 5-Phenyl-[1,2,3]thiadiazole-4-carboxylic Acid Methyl Ester

[0807] A solution of ethyl benzoylacetate (1.1 g) in acetonitrile (10mL) is treated with 4-methylbenzenesulfonyl azide (1.3 g) andtriethylamine (1.6 g). After stirring overnight at room temperature, thereaction is concentrated under reduced pressure and the resulting crudeproduct is dissolved in ethyl acetate and washed with 1N sodiumhydroxide. The organic layer is then dried over anhydrous magnesiumsulfate, filtered and concentrated under reduced pressure to yield ayellow oil. This oil is taken into dichloromethane and filtered througha pad of hydrous magnesium silicate, eluting with dichloromethane togive the partially purified diazoketone as a colorless oil. A sample ofthe diazoketone from above (1.2 g) is dissolved in toluene (25 mL) andtreated with2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (2.8g) and the reaction is heated to reflux. After 3 hours, the reaction iscooled to room temperature, loaded onto a pad of silica gel and elutedwith dichloromethane. After removing the solvent under reduced pressure,the resulting oil is purified by chromatography over silica gel (30%diethyl ether in petroleum ether is used as the eluant) and thenrecrystallized from hexanes to give the desired product as pale yellowneedles.

[0808] Using the above procedure and appropriate starting materials thefollowing compound was prepared:

[0809] 5-Phenyl-[1,2,3]thiadiazole-4-carboxylic acid ethyl ester

[0810] 5-Methyl-[1,2,3]thiadiazole-4-carboxylic acid methyl ester

EXAMPLE 50 Ethyl Benzoylacetate Semicarbazide

[0811] Ethyl benzoylacetate (5.0 g) is dissolved in methanol (10 mL) andadded rapidly to a hot solution of semicarbazide hydrochloride (29 g) inwater (130 mL). To this is added pyridine (4.1 g) and after heating toreflux for 5 minutes, the reaction mixture is cooled to −20° C.overnight. The resulting solid semicarbazone is collected by filtration,washed with water and then diethyl ether to give the desired product aswhite crystals.

[0812] Using the above procedure and appropriate starting materials thefollowing compound was prepared:

[0813] Ethyl (Z)-3-[(aminocarbonyl)hydrazono]-4,4,4-trifluorobutanoate

[0814] 3-[(Z)-2-(Aminocarbonyl)hydrazono]-3-phenylpropanoic acid ethylester

[0815] 3-[(E)-2-(Aminocarbonyl)hydrazono]-3-(3-furyl)propanoic acidethyl ster

EXAMPLE 51 5-Phenyl-[1,2,3]thiadiazole-5-carboxylic Acid Ethyl Ester

[0816] A solution of ethyl benzoylacetate semicarbazone (2.5 g) in neatthionyl chloride (5 mL) is stirred at 0° C. for 1 hour. Dichloromethaneis then added (25 mL), the excess thionyl chloride is destroyed slowlywith saturated aqueous sodium bicarbonate. The precipitate which formson quenching is removed by filtration and the filtrate is extracted withdichloromethane. Pooled organic extracts are dried over anhydrousmagnesium sulfate, filtered and concentrated under reduced pressure.

[0817] Chromatography over silica gel (50% hexanes in dichloromethane isused as the eluant) affords the desired product as a colorless oil.

[0818] Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

[0819] 4-Methyl-[1,2,3]thiadiazole-5-carboxylic acid methyl ester

[0820] 4-Phenyl-[1,2,3]thiadiazole-5-carboxylic acid ethyl ester

[0821] 4-Furan-3-yl-[1,2,3]thiadiazole-5-carboxylic acid ethyl ester

EXAMPLE 52 4-Methyl-[1,2,3]thiadiazole-5-carboxylic Acid

[0822] 4-Methyl-[1,2,3]thiadiazole-5-carboxylic acid methyl ester (1.7g) is dissolved in methanol (15 mL) and treated with 1N sodium hydroxide(16 mL). After stirring at room temperature for 1 hour, the reaction istreated with concentrated hydrochloric acid (1.5 mL) and concentratedunder reduced pressure. The resulting turbid aqueous layer is extractedtwice with diethyl ether and the pooled organic layers are dried overanhydrous magnesium sulfate, filtered and concentrated under reducedpressure to give the desired compound as a white powder.

[0823] Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

[0824] 3-Ethoxycarbonylmethoxy-benzoic acid

[0825] 5-Furan-3-yl-[1,2,3]thiadiazole-4-carboxylic acid

[0826] Thiazole-4-carboxylic acid

[0827] 4-Methyl-[1,2,3]thiadiazole-5-carboxylic acid

[0828] 5-Methyl-[1,2,3]thiadiazole-4-carboxylic acid

EXAMPLE 53 (METHOD 25) Trifluoro-Methanesulfonic Acid4-chloro-5-methoxy-2-nitro-phenyl Ester

[0829] To a solution of 4-chloro-5-methoxy-2-nitro-phenol (6.5 g) indichloromethane (150 mL) at 0° C. under an atmosphere of argon is addedtriethylamine (10 g) and then a solution of trifluoro-methanesulfonicanhydride (13.5 g) in dichloromethane (30 mL). The solution is stirredat 0° C. for 10 minutes, and is then diluted with dichloromethane andwashed successively with saturated aqueous sodium bicarbonate andsaturated aqueous sodium chloride. After drying over anhydrous sodiumsulfate the solvent is removed by evaporation under reduced pressure andthe residue is dissolved in a solution of 20% dichloromethane in hexanesand passed through a short column of hydrous magnesium silicate (20%dichloromethane in hexanes is used as the eluant). Product containingfractions are pooled and the solvents removed by evaporation underreduced pressure to give the desired product as a yellow oil.

[0830] Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

[0831] Trifluoro-methanesulfonic acid 4-chloro-5-methoxy-2-nitro-phenylester

[0832] Trifluoro-methanesulfonic acid 4-chloro-2-nitro-phenyl ester

[0833] Trifluoro-methanesulfonic acid 2-chloro-6-nitro-phenyl ester

EXAMPLE 54 (METHOD 26)[4-(3-Dimethylamino-benzoylamino)-phenyl]-carbamic Acid T-Butyl Ester

[0834] A solution of [4-(3-amino-benzoylamino)-phenyl]-carbamic acidt-butyl ester (505 mg), sodium cyanoborohydride (250 mg), acetic acid (3drops) and 40 % aqueous formaldehyde (4 mL) in 1:2tetrahydrofuran-methanol (15 mL) is stirred for 15 minutes, and thenpoured into saturated aqueous sodium bicarbonate and extracted intoethyl acetate. The ethyl acetate solution is dried over anhydrouspotassium carbonate and concentrated under reduced pressure to give asolid which is recrystallized from acetonitrile to provide a pale pinkcrystalline solid.

[0835] Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

[0836] [4-(3-Dimethylamino-benzoylamino)-phenyl]-carbamic acidtert-butyl ester

[0837] (3-Bromo-5-trifluoromethyl-phenyl)-dimethyl-amine

[0838] N-(3-Chloro-5-dimethylamino-phenyl)-acetamide

EXAMPLE 55 (METHOD 27) N-(4-Aminophenyl)-2-hydroxybenzamide

[0839] To a solution of 2-(4-aminophenylcarbamoyl) phenyl acetate (580mg) in methanol (10 mL) is added saturated sodium bicarbonate (2 mL) andwater (3 mL). The mixture is heated at 80° C. for 30 minutes, thenpoured into half-saturated aqueous sodium chloride and extracted withethyl acetate. The ethyl acetate solution is dried over anhydrous sodiumsulfate and concentrated under reduced pressure to give an oil which isthen triturated with diethyl ether to provide the desired product as awhite solid.

EXAMPLE 56 (METHOD 28) [4-{3-(Hydroxybenzoylamino)phenyl}Carbamic AcidT-Butyl Ester

[0840] To a solution of of 3-(4-aminophenylcarbamoyl) phenyl acetate(4.34 g) in methanol (75 mL) is added 0.1 N aqueous sodium hydroxide (25mL) and tetrahydrofuran (25 mL). This solution is heated at 40° C. for30 minutes, then cooled, poured into 1 M hydrochloric acid and extractedwith ethyl acetate. The ethyl acetate solution is dried over anhydroussodium sulfate and concentrated under reduced pressure to give a whitesolid, which is further purified by trituration with diethyl ether.

EXAMPLE 57 (METHOD 29) N-(4-Aminophenyl)-2-hydroxymethylbenzamide

[0841] To a solution of N-(4-aminophenyl)phthalimide (332 mg) intetrahydrofuran (4 mL) is added lithium borohydride (1.0 g) and themixture is stirred for 1 hour at 25° C. The mixture is poured into waterand extracted into ethyl acetate. The ethyl acetate solution is driedover anhydrous sodium sulfate and concentrated under reduced pressure togive a white foam, which when triturated with diethyl ether provides thedesired product as a white powder.

EXAMPLE 58 (METHOD 30) (3-Chloro-5-dimethylamino-phenyl)-carbamic AcidTert-Butyl Ester

[0842] To a solution of (3-amino-5-chloro-phenyl)-carbamic acidtert-butyl ester (0.32 g) in toluene (10 mL) is added aqueousformaldehyde (37%, 1.5 mL) then 10% palladium on carbon (0.50 g) and themixture is stirred under an atmosphere of hydrogen for approximately 15hours. The solution is then filtered through diatomaceous earth and thefiltrate is concentrated under reduced pressure. The residue ischromatographed over silica gel (50% dichloromethane in hexanes is usedas the eluant) to provide the desired product as a white solid.

EXAMPLE 59 (METHOD 35)N-(4-{3-[3,5-Dichloro-4-(2-hydroxy-ethoxy)-phenyl]-thioureido)-phenyl}-acetamide

[0843] To a solution of acetic acid2-{4-[3-(4-acetylamino-phenyl)-thioureido]-2,6-dichloro-phenoxy}-ethylester (0.16 g) in a 1:1 mixture of tetrahydrofuran and methanol (2.5 mL)is added 1N aqueous sodium hydroxide (1 mL) and the mixture is stirredfor approximately 2 hours at room temperature. The solution is thenpoured into 2 M aqueous hydrochloric acid (3 mL), extracted into ethylacetate, and the extracts are dried over anhydrous sodium sulfate. Thesolvent is removed by evaporation under reduced pressure and the residueis triturated with diethyl ether to provide the desired product as awhite solid.

EXAMPLE 60 (METHOD 36){4-[3-(4-Acetylamino-phenyl)-thioureido]-2,6-dichloro-phenoxy}-aceticAcid

[0844] To a solution of(4-[3-(4-acetylamino-phenyl)-thioureido]-2,6-dichloro-phenoxy)-aceticacid ethyl ester (0.29 g) in a 1:1 mixture of tetrahydrofuran andmethanol (4 mL) is added 1N aqueous sodium hydroxide (2 mL) and themixture is stirred for approximately 2 hours at room temperature. Thesolution is then poured into 2 M aqueous hydrochloric acid. (5 mL),extracted into ethyl acetate, and the extracts are dried over anhydroussodium sulfate. The solvent is removed by evaporation under reducedpressure and the residue is triturated with diethyl ether to provide thedesired product as a white solid.

[0845] Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

[0846]{4-[3-(4-Acetylamino-phenyl)-thioureido]-2,6-dichloro-phenoxy}-aceticacid

[0847]{2-[3-(4-Acetylamino-phenyl)-thioureido]-4-chloro-5-methoxy-phenoxy}-aceticacid

[0848]{4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro-5-methoxy-phenoxy}-aceticacid

EXAMPLE 61 (METHOD 37) Benzoic acid2-{4-[3-(4-acetylamino-phenyl)-thioureido]-2,6-dichloro-phenoxy{-ethylEster.

[0849] To an ice cooled solution ofN-(4-{3-[3,5-dichloro-4-(2-hydroxy-ethoxy)-phenyl]-thioureido}-phenyl)-acetamide(0.20 g) in pyridine (2 mL) and tetrahydrofuran (0.5 mL) is addedbenzoyl chloride (0.08 g) and the mixture is stirred at 0° C. for 1.5hours. The mixture is then diluted with ethyl acetate, washedsuccessively two times with 2% aqueous hydrochloric acid, once withsaturated aqueous sodium chloride, then dried over anhydrous sodiumsulfate. After removal of the solvent under reduced pressure the residueis chromatographed over silica gel (5% methanol in dichloromethane isused as the eluant) and product containing fractions are combined,evaporated under reduced pressure, and the residue is recrystallizedfrom acetone-hexanes to provide the desired product as a white powder.

EXAMPLE 62 (METHOD 38) Methanesulfonic acid2-{4-[3-(4-acetylamino-phenyl)-thioureido]-2,6-dichloro-phenoxy}-ethylEster

[0850] To an ice cooled solution ofN-(4-(3-[3,5-dichloro-4-(2-hydroxy-ethoxy)-phenyl]-thioureido}-phenyl)-acetamide(0.20 g) in pyridine (2 mL) and tetrahydrofuran (0.5 mL) is addedmethanesulfonyl chloride (0.11 g) and the solution is stirred at 0° C.for 45 minutes. The reaction mixture is then diluted with ethyl acetate,washed successively twice with 2% aqueous hydrochloric acid, once withsaturated aqueous sodium chloride, and then dried over anhydrousmagnesium sulfate. After removing the solvents by evaporation underreduced pressure the resulting residue is recrystallized fromacetone-hexanes to give the desired product as a white powder.

EXAMPLE 63 (METHOD 39)N-{4-(3-[3,5-Dichloro-4-(2-dimethylamino-ethoxy)-phenyl]-thioureido}-phenyl)-acetamide

[0851] To a solution of methanesulfonic acid2-(4-[3-(4-acetylamino-phenyl)-thioureido]-2,6-dichlorophenoxy)-ethylester (0.33 g) in tetrahydrofuran (6 mL) is added aqueous dimethyl-amine(8.8 M, 0.5 mL) and the mixture is stirred at room temperature for 5days. The reaction mixture is then diluted with ethyl acetate, thenwashed with saturated aqueous sodium chloride and dried over anhydrousmagnesium sulfate. After removal of the solvent under reduced pressurethe residue is chromatographed over silica gel (pure methanol is used asthe eluant). Pooled product containing fractions are evaporated underreduced pressure and the residue is recrystallized from acetonitrile toprovide the desired product as a white powder.

[0852] Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

[0853]N-(4-{3-[3,5-Dichloro-4-(2-dimethylamino-ethoxy)-phenyl]-thioureido}-phenyl)-acetamide

[0854] Benzoic acid2-(4-[3-(4-acetylamino-phenyl)-thioureido]-2,6-dichloro-phenoxy}-ethylester

EXAMPLE 64 (METHOD 40) Furan-2-carboxylic Acid(4-{3-[4-(1-amino-ethyl)-3-chloro-phenyl]-thioureido}-phenyl)-amide

[0855] To a solution of tin(II) chloride dihydrate (0.25 g) in methanol(2.5 mL) is added furan-2-carboxylic acid{4-(3-[4-(1-azido-ethyl)-3-chloro-phenyl]-thioureido}-phenyl)-amide(0.22 g) and the solution is stirred for approximately 15 hours at roomtemperature. The solution is then diluted with ethyl acetate, washedsuccessively with saturated aqueous sodium bicarbonate then saturatedaqueous sodium chloride, then dried over anhydrous sodium sulfate. Afterremoval of the solvent by evaporation under reduced pressure the residueis chromatographed over silica gel (8% methanol in dichloromethanecontaining 1% triethylamine is used as the eluant) to provide thedesired product as a yellow solid.

EXAMPLE 65 (METHOD 41) [1,2,3]Thiadiazole-4-carboxylic Acid(4-isothiocyanato-phenyl)-amide

[0856] To a ice cooled solution of 1,1′-thiocarbonyldiimidazole (7.28 g)in tetrahydrofuran (50 mL) is added [1,2,3]-thiadiazole-4-carboxylicacid (4-amino-phenyl) amide (9.0 g) in tetrahydrofuran (100 mL). Afterapproximately one hour the solvent is removed by evaporation and theresidue is dissolved in ethyl acetate. Diethyl ether is added toprecipitate the crude product, which is then collected by filtration,dissolved in dichloromethane, and passed through a plug of hydrousmagnesium silicate. After removal of solvents, the residue isrecrystallized from ethyl acetate-hexanes to provide the desired productas a slightly yellow solid.

[0857] Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

[0858] 2-Fluoro-N-(4-isothiocyanato-phenyl)-benzamide

[0859] Furan-2-carboxylic acid (4-isothiocyanato-phenyl)-amide

[0860] [1,2,3]Thiadiazole-4-carboxylic acid(4-isothiocyanato-phenyl)-amide

[0861] Thiazole-4-carboxylic acid (4-isothiocyanato-phenyl)-amide

EXAMPLE 66 (METHOD 42)N,N-Dimethyl-5-trifluoromethyl-benzene-1,3-diamine

[0862] To a solution of 3-amino-5-bromo-benzotrifluoride (1.0 g) indegassed (argon) tetrahydrofuran (2 mL) is addedbis-(tri-o-tolylphosphino)palladium (0.15 g), a solution ofdimethylamine in tetra-hydrofuran (2M, 4.2 mL), and a solution oflithium bis(trimethylsilyl)amide in tetrahydrofuran (1M, 10.4 mL). Thereaction mixture is heated in a sealed vessel to 100° C. forapproximately 2.5 hours to complete the reaction. The mixture is thencooled to room temperature, quenched by addition of water, and dilutedwith ethyl acetate. The product is extracted three times into 5% aqueoushydrochloric acid, and pooled acidic extracts are then basified withcooling by addition of 5N aqueous sodium hydroxide. This basic solutionis then extracted with ethyl acetate, and these pooled organic extractsare washed with saturated aqueous sodium chloride, dried over anhydrousmagnesium sulfate, and evaporated to dryness under reduced pressure. Theresulting residue is chromatographed over silica gel (20-30% ethylacetate in hexanes is used as the eluant) to provide the desired productas a slightly tinted solid.

[0863] Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

[0864] 3-(4-Methyl-piperazin-1-yl)-5-trifluoromethyl-phenylamine

[0865] 3-Morpholin-4-yl-5-trifluoromethyl-phenylamine

[0866] 3-Piperidin-1-yl-5-trifluoromethyl-phenylamine

[0867] 3-Pyrrolidin-1-yl-5-trifluoromethyl-phenylamine

[0868] N,N-Dimethyl-5-trifluoromethyl-benzene-1,3-diamine

[0869] N-Isobutyl-N-methyl-5-trifluoromethyl-benzene-1,3-diamine

[0870] N-Butyl-N-methyl-5-trifluoromethyl-benzene-1,3-diamine

EXAMPLE 67 (METHOD 43) (3-Isobutyl-5-trifluoromethyl-phenyl)-carbamicAcid Tert-Butyl Ester

[0871] To a sealed tube containing tetrahydrofuran (5 mL) that is cappedwith a rubber septum and cooled in a dry ice-acetone bath is bubbledisobutylene for about 5 minutes. A solution of 9-borabicyclo[3.3.1]nonane in tetrahydrofuran (0.5 M, 11 mL) is added, the vessel is sealedwith a teflon cap, slowly warmed to room temperature and kept at roomtemperature for approximately 2.5 hours. The mixture is then re-cooledin a dry ice-acetone bath, the teflon cap is replaced by a rubberseptum, and argon is bubbled through the mixture with venting to removedthe excess isobutylene. A solution of(3-bromo-5-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (1.7g) in tetrahydrofuran (12 mL) is added, followed by[1,1′-bis(diphenylphosphino)-ferrocene]palladium(II)chloride-dichlormethane complex (0.12 g), and then 3N aqueous sodiumhydroxide. The vessel is again sealed with the teflon cap and is thenheated to 65° C. for approximately 15 hours. The mixture is then cooledto room temperature, diluted with hexanes, washed with water, saturatedaqueous sodium chloride, dried over anhydrous magnesium sulfate, andevaporated under reduced pressure. The resulting oil is chromatographedover silica gel (5% ethyl acetate in hexanes is used as the eluant) toprovide the desired product as a white powder.

[0872] Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

[0873] [3-(2-Methyl-butyl)-5-trifluoromethyl-phenyl]-carbamic acidtert-butyl ester

[0874] (3-Isobutyl-5-trifluoromethyl-phenyl)-carbamic acid tert-butylester

EXAMPLE 68 (METHOD 44) 2-(3,5-Dichloro-phenylsulfanyl)-ethylamine

[0875] To a solution of (3,5-dichlorophenylthio)acetonitrile (1.2g) in3.0 mL of ethylene glycol dimethyl ether is added 0.61 mL of 10M boranedimethyl sulfide complex and the mixture heated at reflux for 0.5 hours.The reaction is cooled in an ice bath and 2.0 mL of water and 2.0 mL ofconcentrated hydrochloric acid is added. This mixture is heated atreflux for 0.5 hr. The clear solution is then cooled and basified with5N sodium hydroxide and extracted with ether. The ether extract is driedover potassium carbonate, filtered and concentrated to give 1.0 g of acolorless oil.

[0876] Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

[0877] 2-(3-Bromo-phenylsulfanyl)-ethylamine

[0878] 2(4-Bromo-phenoxy)-ethylamine

[0879] 2-(4-Iodo-phenoxy)-ethylamine

[0880] 2-(3,4-Dichloro-phenoxy)-ethylamine

[0881] 2-(3-Chloro-phenylsulfanyl)-ethylamine

[0882] 2-(3,4-Dichloro-phenylsulfanyl)-ethylamine

[0883] 3-(4-Bromo-phenyl)-propylamine

[0884] 2-(2-Fluoro-phenoxy)-ethylamine

[0885] 2-(2-Chloro-phenoxy)-ethylamine

[0886] 2-(3-Bromo-phenoxy)-ethylamine

[0887] 2-(3-Fluoro-phenoxy)-ethylamine

[0888] 2-(3-Iodo-phenoxy)-ethylamine

[0889] 2-(3,5-Dichloro-phenylsulfanyl)-ethylamine

[0890] 2-Phenylsulfanyl-ethylamine

[0891] 1-(2-Chloro-phenyl)-ethylamine

EXAMPLE 69 (METHOD 45) N-(1-Naphthalen-2-yl-ethyl)-formamide

[0892] A mixture of 2-acetylnaphthylene (3.0 g), ammonium formate (11.0g), formic acid (3.3 mL), and formamide (3.5 mL) is heated at 190° C.for 3 hours. The mixture is cooled, poured into water and extracted withether. The ether extract is dried with anhydrous potassium carbonate,filtered and concentrated to give a yellow oil, which is crystallizedfrom toluene-hexanes to give a white solid, 1.97 g.

[0893] Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

[0894] N-[1-(4-Fluoro-phenyl)-2-methyl-propyl]-formamide

[0895] N-(1-Naphthalen-2-yl-ethyl)-formamide

EXAMPLE 70 (METHOD 46) 1-(2-Naphthyl)ethylamine

[0896] A mixture of N-(1-naphthalen-2-yl-ethyl)-formamide (1.12 g),ethanol (10 mL) and 5 N sodium hydroxide (10 mL) is heated at reflux for1 hour. The solution is cooled, poured into water and extracted withether. The ether solution is dried with anhydrous potassium carbonate,filtered and concentrated to give the product (0.95 g) as a pale yellowoil.

[0897] Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

[0898] 1-(3-Trifluoromethyl-phenyl)-ethylamine

[0899] 1-(4-Fluoro-phenyl)-2-methyl propylamine

[0900] [3-(1-Amino-ethyl)-phenyl]-dimethyl-amine

[0901] 3-(1-Amino-ethyl)-benzonitrile

EXAMPLE 71 (METHOD 47) 1-(3-Trifluoromethyl-phenyl)-ethanoneO-methyl-oxime

[0902] Methoxylamine hydrochloride (2.33 g) is added to a solution of3′-(trifluoromethyl)-acetophenone (1.5 g) in ethanol (20 mL) andpyridine (2 mL). The solution is heated at reflux for 45 minutes. Thereaction mixture is then cooled, concentrated under reduced pressure andpartitioned between water and ethyl acetate. The aqueous layer isextracted with ethyl acetate. The combined organic layers are washedwith saturated aqueous sodium chloride, dried over anhydrous magnesiumsulfate and concentrated under reduced pressure to give the desiredproduct as a colorless oil (1.61 g).

[0903] Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

[0904] 3,5-Bis-trifluoromethyl-benzaldehyde oxime

[0905] 1-(4-Fluoro-phenyl)-propan-1-one O-methyl-oxime

[0906] 1-(2-Chloro-phenyl)-ethanone O-methyl-oxime

[0907] 1-(3-Bromo-phenyl)-ethanone O-methyl-oxime

[0908] 1-(3-Chloro-phenyl)-ethanone O-methyl-oxime

[0909] 1-p-Tolyl-ethanone O-methyl-oxime

[0910] 1-(4-Fluoro-phenyl)-pentan-1-one O-methyl-oxime

[0911] 1-(4-Fluoro-phenyl)-2-phenyl-ethanone O-methyl-oxime

[0912] 1-p-Tolyl-ethanone O-methyl-oxime

[0913] 3-(1-Methoxyimino-ethyl)-benzonitrile

[0914] 4-(1-Methoxyimino-ethyl)-benzonitrile

[0915] 1-(4-Methoxy-phenyl)-ethanone O-methyl-oxime

[0916] 1-(2-Methoxy-phenyl)-ethanone O-methyl-oxime

[0917] 1-(4-Dimethylamino-phenyl)-ethanone O-methyl-oxime

[0918] 1-(2-Trifluoromethyl-phenyl)-ethanone O-methyl-oxime

[0919] 1-(3-Methoxy-phenyl)-ethanone O-methyl-oxime

[0920] 1-(3-Trifluoromethyl-phenyl)-ethanone O-methyl-oxime

[0921] 1-(4-Trifluoromethyl-phenyl)-ethanone O-methyl-oxime

[0922] 1-Furan-2-yl-ethanone 0-methyl-oxime

[0923] 1-Pyridin-4-yl-ethanone 0-methyl-oxime

[0924] 1-(1-Methyl-1H-pyrrol-2-yl)-ethanone O-methyl-oxime

[0925] 1-Thiophen-3-yl-ethanone O-methyl-oxime

[0926] (4-Fluoro-phenyl)-phenyl-methanone O-methyl-oxime

[0927] 1-(4-methoxyphenyl)ethanone O-methyloxime

[0928] 1-(3-Chloro-4-methoxy-phenyl)-ethanone O-methyl-oxime

[0929] 4-(1-Methoxyimino-ethyl)-benzenesulfonamide

[0930] 4-(1-Methoxyimino-ethyl)-N,N-dimethyl-benzenesulfonamide

[0931] 1-[4-(Piperidine-1-sulfonyl)-phenyl]-ethanone O-methyl-oxime

[0932] 4-(1-Methoxyimino-ethyl)-N,N-dipropyl-benzenesulfonamide

[0933] 2-Fluoro-N-[4-(1-methoxyimino-ethyl)-phenyl]-benzamide

[0934] 1-(3,5-Bis-trifluoromethyl-phenyl)-ethanone O-methyl-oxime

[0935] 1-[4-(1H-Imidazol-1-yl)phenyl]-1-ethanone, O-methyloxime

[0936] 1-[4-(Trifluoromethyl)phenyl]-1-ethanone, O-methyloxime

[0937] 1-[1,1′-Biphenyl]-4-yl-1-ethanone, O-methyloxime

[0938] 1-(4-Methylphenyl)-1-ethanone, O-methyloxime

[0939] 1-[4-fluoro-3-(trifluoromethyl)phenyl]ethanone O-methyloxime

[0940] 1-[3,5-bis(trifluoromethyl)phenyl]ethanone O-benzyloxime

[0941] 1-[4-chloro-3-(trifluoromethyl)phenyl]ethanone O-methyloxime

[0942] 1-[3-fluoro-5-(trifluoromethyl)phenyl]ethanone O-methyloxime

[0943] 1-[2-fluoro-4-(trifluoromethyl)phenyl]ethanone O-methyloxime

[0944] 1-[2-fluoro-5-(trifluoromethyl)phenyl]ethanone O-methyloxime

[0945] 1-(2,4-dichlorophenyl)ethanone O-methyloxime

[0946] 1-(2,4-dimethylphenyl)ethanone O-methyloxime

[0947] 1-[2,4-bis(trifluoromethyl)phenyl]ethanone O-methyloxime

[0948] 1-(3-bromophenyl)ethanone O-methyloxime

[0949] 1-(3-methylphenyl)ethanone O-methyloxime

[0950] 1-[4-(4-morpholinyl)phenyl]ethanone O-methyloxime

[0951] 1-(2-chloro-4-fluorophenyl)ethanone O-methyloxime

[0952] 1-(4-bromo-2-fluorophenyl)ethanone O-methyloxime

[0953] 1-(3,4-difluorophenyl)ethanone O-methyloxime

[0954] 1-[3-(trifluoromethyl)phenyl]ethanone O-methyloxime

[0955] 1-[2-(trifluoromethyl)phenyl]ethanone O-methyloxime

[0956] 1-(2,4-difluorophenyl)ethanone O-methyloxime

[0957] 1-[3-fluoro-4-(trifluoromethyl)phenyl]ethanone O-methyloxime

[0958] 1-(3,4-dichlorophenyl)ethanone O-methyloxime

[0959] 1-[4-fluoro-2-(trifluoromethyl)phenyl]ethanone O-methyloxime

[0960] 1-(3-chloro-4-fluorophenyl)ethanone O-methyloxime

[0961] 1-(4-chloro-3-fluorophenyl)ethanone O-methyloxime

[0962] 1-(2,5-ditluorophenyl)ethanone O-methyloxime

[0963] 1-(2-bromo-4-fluorophenyl)ethanone O-methyloxime

[0964] 1-(3,4-dibromophenyl)ethanone O-methyloxime

[0965] 1-(2-bromophenyl)ethanone O-methyloxime

EXAMPLE 72 (METHOD 48) 1-(2-Trifluoromethyl-phenyl)-ethylamine

[0966] Sodium borohydride (1.17 g) is added slowly to a flask containingzirconium tetrachloride (1.8 g) in tetrahydrofuran (27 mL). A solutionof 1-(2-trifluoromethyl-phenyl)-ethanone O-methyl-oxime (1.34 g) intetrahydrofuran (7.7 mL) is added and the resulting solution is stirredat 25° C. for 12 hours. The reaction mixture is then cooled to 0° C. andwater (16 mL) is slowly added. Excess ammonium hydroxide is added andthe solution is extracted twice with ethyl acetate. The organic portionis washed twice with 1N hydrochloric acid. The aqueous (acid) layer isbasified with sodium hydroxide and extracted twice with ethyl acetate.The organic layer is then washed with saturated aqueous sodium chlorideand dried over anhydrous magnesium sulfate. The solvent is removed underreduced pressure to provide the desired product as a yellow oil (0.20g).

[0967] Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

[0968] 1-(3-Methoxy-phenyl)-ethylamine

[0969] 1-(4-Fluoro-phenyl)-propylamine

[0970] 1-Naphthalen-2-yl-ethylamine

[0971] 4-(1-Amino-ethyl)-benzonitrile

[0972] 1-(4-Trifluoromethyl-phenyl)-ethylamine

[0973] 1-(4-Methoxy-phenyl)-ethylamine

[0974] 1-Prop-2-ynyl-pyrrolidine

[0975] 1-(2-Methoxy-phenyl)-ethylamine

[0976] 1-m-Tolyl-ethylamine

[0977] 1-(2-Bromo-phenyl)-ethylamine

[0978] 1-o-Tolyl-ethylamine

[0979] C-(4-Fluoro-phenyl)-C-phenyl-methylamine

[0980] 1-(4-Fluoro-phenyl)-pentylamine

[0981] 1-(4-Fluoro-phenyl)-2-phenyl-ethylamine

[0982] 1-(2-Trifluoromethyl-phenyl)-ethylamine

[0983] 1-(3-Bromo-phenyl)-ethylamine

[0984] 1-(3-Chloro-phenyl)-ethylamine

[0985] [4-(1-Amino-ethyl)-phenyl]-dimethyl-amine

[0986] 1-(1-Methyl-1H-pyrrol-2-yl)-ethylamine

[0987] 1-Thiophen-3-yl-ethylamine

[0988] 1-[3,5-bis(trifluoromethyl)phenyl]propylamine

[0989] 1-[3,5-bis(trifluoromethyl)phenyl]-1-butanamine or1-[3,5-bis(trifluoromethyl)phenyl]butylamine

[0990] 1-[3,5-bis(trifluoromethyl)phenyl]-1-pentanamine

[0991] 1-(4-methylphenyl)ethanamine

[0992] 1-[3-(trifluoromethyl)phenyl]ethylamine

[0993] 1-[4-(trifluoromethyl)phenyl]ethylamine

[0994] 1-(3-methylphenyl)ethanamine

[0995] 1-(3,4-dichlorophenyl)ethanamine

[0996] 1-(2-Bromo-phenyl)-ethylamine

[0997] 1-(2-Trifluoromethyl-phenyl)-ethylamine

[0998] 1-(3-Bromo-phenyl)-ethylamine

[0999] 1-(3-Chloro-4-methoxy-phenyl)-ethylamine

[1000] 4-(1-Amino-ethyl)-N,N-dimethyl-benzenesulfonamide

[1001] 1-[4-(Piperidine-1-sulfonyl)-phenyl]-ethylamine

[1002] 1-Quinolin-6-yl-ethylamine

[1003] 1-(3,5-Bis-trifluoromethyl-phenyl)-ethylamine

[1004] 4-[(1 S)-1-aminoethyl]benzonitrile

[1005](S)-alpha-Methyl-3,5-bis(trifluoromethyl)-benzenemethanamine(S)-alpha-Methyl-3,5-bis(trifluoromethyl)-benzenemethanamine

[1006] 1-Biphenyl-4-yl-ethylamine

[1007] 1-(4-Fluoro-phenyl)-ethyl amine

[1008] 1-[4-fluoro-3-(trifluoromethyl)phenyl]ethanamine

[1009] 1-[4-chloro-3-(trifluoromethyl)phenyl]ethanamine

[1010] N-{4-[(1R)-1-aminoethyl]phenyl}-1,2,3-thiadiazole-4-carboxamide

[1011] N-{4-[(1S)-1-aminoethyl]phenyl}-1,2,3-thiadiazole-4-carboxamide

[1012] 1-[3-fluoro-5-(trifluoromethyl)phenyl]ethylamine

[1013] 1-[2-fluoro-4-(trifluoromethyl)phenyl]ethylamine

[1014] 1-[2-fluoro-5-(trifluoromethylDphenyl]ethylamine

[1015] 1-(2,4-dichlorophenyl)ethylamine

[1016] 1-(2,4-dimethylphenyl)ethylamine

[1017] 1-[2,4-bis(trifluoromethyl)phenyl]ethylamine

[1018] 1-(2-chloro-4-fluorophenyl)ethylamine

[1019] 1-(3,4-difluorophenyl)ethylamine

[1020] 1-(4-bromo-2-fluorophenyl)ethylamine

[1021] 1-(3-fluorophenyl)ethylamine

[1022] 1-(2,4-difluorophenyl)ethylamine

[1023] 1-[3-fluoro-4-(trifluoromethyl)phenyl]ethylamine

[1024] 1-[4-fluoro-2-(trifluoromethyl)phenyl]ethylamine

[1025] 1-(3-chloro-4-fluorophenyl)ethylamine

[1026] 1-(4-chloro-3-fluorophenyl)ethylamine

[1027] 1-(3,4-dibromophenyl)ethylamine

[1028] 1-(2-bromo-4-fluorophenyl)ethanamine1-(2-bromo-4-fluorophenyl)ethylamine

EXAMPLE 73 (METHOD 49) (2-Fluoro-5-trifluoromethyl-phenoxy)-acetonitrile

[1029] A solution of 2-fluoro-5-trifluoromethylphenol (25 g) in reagentgrade acetone (0.55 L) is treated with solid potassium carbonate (7.7 g)followed by the rapid addition of neat bromoacetonitrile (10 mL). Theheterogenous mixture is stirred vigorously for approximately 20 hourswhereupon it is poured into water and extracted into diethyl ether. Thecombined ether extracts are washed with saturated sodium chloride anddried over anhydrous potassium carbonate. Filtration and concen-trationunder reduced pressure gives a pale orange solid which is thenchromatographed on silica gel, eluting with dichloromethane, to give thedesired product as white solid (28.3 g). Using the above procedure andappropriate starting materials the following compounds were prepared:

[1030] (3-Bromo-phenylsulfanyl)-acetonitrile

[1031] (3-Chloro-phenylsulfanyl)-acetonitrile

[1032] (4-Iodo-phenoxy)-acetonitrile

[1033] (3-Trifluoromethyl-phenylsulfanyl)-acetonitrile

[1034] (3,5-Dichloro-phenylsulfanyl)-acetonitrile

[1035] (3,4-Dichloro-phenylsulfanyl)-acetonitrile

[1036] (3,4-Dichloro-phenoxy)-acetonitrile

[1037] (2-Fluoro-phenoxy)-acetonitrile

[1038] (3-Fluoro-phenoxy)-acetonitrile

[1039] (2-Chloro-phenoxy)-acetonitrile

[1040] (3-Bromo-phenoxy)-acetonitrile

[1041] (2-Fluoro-5-trifluoromethyl-phenoxy)-acetonitrile

[1042] (3-Iodo-phenoxy)-acetonitrile

[1043] (4-Bromo-phenoxy)-acetonitrile

EXAMPLE 74 (METHOD 50) 3-Fluoro-5-trifluoromethylphenethylamine tosylate

[1044] A solution of 2.5 g of3-fluoro-5-trifluoromethylphenylacetonitrile and 2.34 g (12.3 mmol) ofp-toluenesulfonic acid in 75 ml of ethylene glycol monomethyl ether ishydrogenated for 3 hours at room temperature at 40 psi, using 200 mg 10%palladium on carbon catalyst. The catalyst is filtered off and thesolvent evaporated to half the volume. Upon standing, thep-toluenesulfonic acid salt of the desired3-fluoro-5-trifluoromethylphenethylamine crystallizes. The whitecrystals, 4.26 g (91%) are collected by filtration.

[1045] Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

[1046] 2-(3,5-Difluoro-phenyl)-ethylamine

[1047] 2-(4-Trifluoromethyl-phenyl)-ethylamine

[1048] 2-(3,4-Difluoro-phenyl)-ethylamine

[1049] 2-(2-Fluoro-phenyl)-ethylamine

[1050] 2-(3-Fluoro-5-trifluoromethyl-phenyl)-ethylamine

[1051] 2-(2-Fluoro-3-trifluoromethyl-phenyl)-ethylamine

[1052] 2-(2,4-Bis-trifluoromethyl-phenyl)-ethylamine

[1053] 2-(4-Fluoro-3-tritluoromethyl-phenyl)-ethylamine

EXAMPLE 75 (METHOD 51)(4-Aminomethyl-2-trifluoromethyl-phenyl)-dimethyl-amine

[1054] A solution of 4-dimethylamino-3-trifluoromethylbenzonitrile (0.35g) in tetrahydrofuran (2 mL) is slowly added to a suspension of lithiumaluminum hydride (0.1 g) in tetrahydrofuran (2 mL) at 0° C. and stirredunder an atmosphere of argon for 2 hours. While at 0° C. water (0.1 mL)is slowly added followed by 5% sodium hydroxide (0.1 mL) and water (0.3mL). The resulting gray solid is filtered and washed withtetrahydrofuran. The filtrates are collected and concentrated underreduced pressure and the resulting oil is chromatographed over silicagel (15% methanol in methylene chloride is used as the eluant) toprovide the desired product as a pale orange oil (0.164 g).

[1055] Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

[1056] 4-Piperidin-1-yl-3-trifluoromethyl-benzylamine

[1057] (4-Aminomethyl-2-trifluoromethyl-phenyl)-dimethyl-amine

[1058] 4-(4-Methyl-piperazin-1-yl)-3-trifluoromethyl-benzylamine

[1059] (3-Aminomethyl-5-trifluoromethyl-phenyl)-dimethyl-amine

[1060] [3-(2-Amino-ethyl)-5-trifluoromethyl-phenyl]-dimethyl-amine

[1061] [4-(2-Amino-ethyl)-2-methyl-phenyl]-dimethyl-amine

EXAMPLE 76 (METHOD 52) 3-Dimethylamino-5-trifluoromethyl-benzaldehyde

[1062] Diisobutylaluminum hydride (10 mL of a 1M solution in methylenechloride) is added dropwise to a solution of3-dimethylamino-5-trifluoromethylbenzonitrile (1.06 g) in methylenechloride (25 mL) at 0° C. and the mixture stirred for 2 hours. Whilestill at 0° C. a saturated aqueous solution of sodium potassium tartrate(8 mL) is slowly added and the solution is stirred for 1.5 hours. Thereaction mixture is then extracted with ethyl acetate, dried overanhydrous magnesium sulfate and concentrated under reduced pressure toprovide the desired product as a yellow solid (0.97 g).

[1063] Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

[1064] 3-Dimethylamino-5-trifluoromethyl-benzaldehyde

[1065] 4-Dimethylamino-3-methyl-benzaldehyde

EXAMPLE 77 (METHOD 53)Dimethyl-[3-(2-nitro-vinyl)-5-trifluoromethyl-phenyl]-amine

[1066] Nitromethane (0.473 g) is added to a solution of3-dimethylamino-5-trifluoromethyl-benzaldehyde (0.885 g) and ammoniumacetate (0.339 g) in acetic acid (3.4 mL) and the solution is heated at110° C. for 6 hours. The reaction mixture is cooled to 0° C. and a solidforms which is filtered and washed with 1:1 water-acetic acid. Thissolid is recrystallized from ethanol to provide the desired product as ared solid (0.39 g).

[1067] Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

[1068] Dimethyl-[3-(2-nitro-vinyl)-5-trifluoromethyl-phenyl]-amine

[1069] Dimethyl-[2-methyl-4-(2-nitro-vinyl)-phenyl]-amine

EXAMPLE 78 (METHOD 54) 3-(4-Bromo-phenyl)-propionitrile

[1070] Diethylazodicarboxylate (5.2 g) is added dropwise to a solutionof 4-bromo-phenethylalcohol (2.01 g), and triphenylphosphine (7.9 g) indiethyl ether (16 mL) at 0° C. The reaction mixture is stirred for 10minutes and a solution of acetone cyanohydrin (2.6 g) in diethyl ether(10 mL) is added. The clear orange solution is stirred for 5 minutes at0° C. and then at 25° C. for 12 hours. The reaction mixture is thenfiltered, and washed with diethyl ether. The filtrate is concentratedunder reduced pressure and chromatographed over silica gel (10% ethylacetate-hexanes is used as the eluant) to provide the desired product asa pale yellow oil (2.04 g).

EXAMPLE 79 (METHOD 55) 3-Dimethylamino-2-isocyano-acrylic Acid EthylEster

[1071] To a solution of ethyl isocyanoacetate (5.0 g) in ethanol (100mL) is added N,N-dimethyl-formamide dimethyl acetal (6.5 g) dropwisewith stirring over 10 minutes. The reaction is stirred for 24 hours andthe ethanol is evaporated. The resulting oil is passed through magnesiumsilicate using 50% ethyl acetate-hexanes as the eluant. The solvents areremoved and the resulting oil is crystallized from ethyl acetate-hexanesto yield light yellow needles, 3.0 g.

EXAMPLE 80 (METHOD 56) 4-Carboethoxythiazole

[1072] A solution of 3-dimethylamino-2-isocyano-acrylic acid ethyl ester(1.0 g) and triethylamine (3.0 g) in tetrahydrofuran (30 mL) is treatedwith gaseous hydrogen sulfide until all starting material is consumed.The mixture is concentrated to an oil and purified by columnchromatography using silica and 25% ethyl acetate-hexanes as the eluant.The purified material (0.61 g) is isolated as an oil.

EXAMPLE 81 (METHOD 34)N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-ureido]-phenyl}-2-fluoro-benzamide

[1073] A suspension of N-(4-amino-phenyl)-2-fluoro-benzamide (0.43 g) inacetonitrile (4 mL) is treated with5-chloro-2,4-dimethoxyphenylisocyanate (0.40 g). The mixture becomes asolution and is allowed to stand for 12 hours. A white solid forms andis collected by filtration (0.79 g). [M+H] 444.

[1074] Using the above procedure and appropriate starting materials thefollowing compounds were prepared: EX NO. M + H COMPOUND NAME 81 445N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-ureido]-phenyl}-2-fluoro-benzamide82 441N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-ureido]-phenyl}-2-methyl-benzamide83 435 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-ureido]- phenyl}-amide 84 443[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(4-chloro-3-trifluoromethyl-phenyl)- ureido]-phenyl}amide 85 453N-{4-[3-(4-Chloro-3-trifluoromethyl-phenyl)-ureido]-phenyl}-2-fluoro-benzamide86 409 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3,5-dichloro-phenyl)-ureido]-phenyl}-amide 87 486N-{4-[3-(3,5-Bis-trifluoromethyl-phenyl)-ureido]-phenyl}-2-fluoro-benzamide88 458 Furan-2-carboxylic acid{4-[3-(3,5-bis-trifluoromethyl-phenyl)-ureido]-phenyl}-amide 89 476[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3,5-bis-trifluoromethyl-phenyl)-ureido]- phenyl}-amide 90 423[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3,4-dichloro-benzyl)-ureido]-phenyl}-amide

EXAMPLE 91(•)N-(5-{[({(1S)1-[3,5-bis(trifluoromethyl)phenyl]ethyl}amino)carbothioyl]amino}-2-pyridinyl)-1,3-thiazole-4-carboxamide

[1075] A mixture ofN-(5-isothiocyanato-2-pyridinyl)-1,3-thiazole-4-carboxamide (0.36 g) and(S)-alpha-methyl-3,5-bis(trifluoromethyl)-benzenemethanamine (0.36 g) iswith acetonitrile (10 mL) until all solids are dissolved. The solutionis allowed d for 12 hours. A white solid forms and is collected byfiltration (0.40 g). 520.

[1076] Using the above procedure and appropriate starting materials thefollowing compounds were prepared: EX NO. M + H COMPOUND NAME 92 506[3-Chloro-5-(3-{4-[([1,2,3]thiadiazole-4-carbonyl)-amino]-phenyl}-thioureido)-phenyl]-carbamic acid tert-butyl ester 93 4091-(5-Chloro-2,4-dimethoxy-phenyl)-3-(4-morpholin-4-yl-phenyl)-thiourea94 3701-(5-Chloro-2,4-dimethoxy-phenyl)-3-(4-methylsulfanyl-phenyl)-thiourea95 338 1-(5-Chloro-2,4-dimethoxy-phenyl)-3-p-tolyl-thiourea 96 414{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenylsulfanyl}-aceticacid 97 3841-(5-Chloro-2,4-dimethoxy-phenyl)-3-[4-(2-hydroxy-ethoxy)-phenyl]-thiourea98 340 1-(5-Chloro-2,4-dimethoxy-phenyl)-3-(4-hydroxy-phenyl)-thiourea99 395N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-N-methyl-acetamide100 381N-{3-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-acetamide101 411{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-carbamic acidethyl ester 102 3191-(2,4-Dimethoxy-phenyl)-3-(4-methoxy-phenyl)-thiourea 103 346N-{4-[3-(2,4-Dimethoxy-phenyl)-thioureido]-phenyl}-acetamide 104 316N-{4-[3-(4-Methoxy-phenyl)-thioureido]-phenyl}-acetamide 105 316N-{4-[3-(2-Methoxy-phenyl)-thioureido]-phenyl}-acetamide 106 351N-{4-[3-(3-Chloro-4-methoxy-phenyl)-thioureido]-phenyl}-acetamide 107351 N-{4-[3-(5-Chloro-2-methoxy-phenyl)-thioureido]-phenyl}-acetamide108 371N-{4-[3-(3,5-Dichloro-4-hydroxy-phenyl)-thioureido]-phenyl}-acetamide109 385N-{4-[3-(3,5-Dichloro-4-methoxy-phenyl)-thioureido]-phenyl}-acetamide110 381N-{4-[3-(4-Chloro-2,5-dimethoxy-phenyl)-thioureido]-phenyl}-acetamide111 389N-{4-[3-(2-Chloro-5-trifluoromethyl-phenyl)-thioureido]-phenyl}-acetamide112 389N-{4-[3-(4-Chloro-3-trifluoromethyl-phenyl)-thioureido]-phenyl}-acetamide113 422 Benzoic acid4-[3-(4-acetylamino-phenyl)-thioureido]-3-hydroxy-phenylester 114 457N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2-methyl-benzamide 115 501 Acetic acid2-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl-carbamoyl}-phenyl ester 116 461N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-4-fluoro-benzamide117 461N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-3-fluoro-benzamide118 461N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide119 473N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2-methoxy-benzamide120 473N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-3-methoxy-benzamide121 473N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-4-methoxy-benzamide122 443N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-benzamide123 417N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-methanesulfonamide124 331 N-{4-[3-(3-Nitro-phenyl)-thioureido]-phenyl}-acetamide 125 3391-(3-Chloro-4-methoxy-phenyl)-3-(3-nitro-phenyl)-thiourea 126 337N-{4-[3-(5-Chloro-2-hydroxy-phenyl)-thioureido]-phenyl}-acetamide 127439 {4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-carbamicacid tert- butyl ester 128 351N-{4-[3-(3-Chloro-4-hydroxy-5-methyl-phenyl)-thioureido]-phenyl}-acetamide129 385N-{4-[3-(3,5-Dichloro-4-hydroxy-2-methyl-phenyl)-thioureido]-phenyl}-acetamide130 318 N-{4-[3-(2,4-Dihydroxy-phenyl)-thioureido]-phenyl}-acetamide 131414N-{4-[3-(2,4-Dimethoxy-5-trifluoromethyl-phenyl)-thioureido]-phenyl}-acetamide132 332N-{4-[3-(2-Hydroxy-4-methoxy-phenyl)-thioureido]-phenyl}-acetamide 133465N-{4-[3-(3,5-Dichloro-4-methoxy-phenyl)-thioureido]-phenyl}-4-fluoro-benzamide134 5003-Acetylamino-N-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-benzamide135 488N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-3-nitro-benzamide136 486N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-3-dimethylamino-benzamide 137 536N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-3-methane-sulfony-amino-benzamide 138 511N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2-trifluoro-methyl-benzamide 139 459N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2-hydroxy-benzamide 140 479N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2,6-difluoro-benzamide 141 4772-Chloro-N-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-benzamide 142 5222-Bromo-N-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-benzamide 143 488N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2-nitro-benzamide 144 445 Pyrazine-2-carboxylic acid{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]- phenyl}-amide 145 4635-Methyl-thiophene-2-carboxylic acid{4-[3-(5-chloro-2,4-dimethoxy-phenyl)- thioureido]-phenyl}-amide 146 494Quinoline-8-carboxylic acid{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]- phenyl}-amide 147 4461-Methyl-1H-pyrrole-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-amide 148 3691-(5-Chloro-2,4-dimethoxy-phenyl)-3-(2-nitro-phenyl)-thiourea 149 3691-(5-Chloro-2,4-dimethoxy-phenyl)-3-(4-nitro-phenyl)-thiourea 150 425N-{4-[3-(5-Bromo-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-acetamide 151376 N-{4-[3-(3,4,5-Trimethoxy-phenyl)-thioureido]-phenyl}-acetamide 152399N-{4-[3-(3,5-Dichloro-2-methoxy-4-methyl-phenyl)-thioureido]-phenyl}-acetamide 153 499 Benzo[b]thiophene-2-carboxylic acid{4-[3-(5-chloro-2,4-dimethoxy-phenyl)- thioureido]-phenyl}-amide 154 483Benzofuran-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-amide 155 444N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-isonicotinamide156 493 Naphthalene-2-carboxylic acid{4-[3-(5-chloro-2,4-dimethoxy-phenyl)- thioureido]-phenyl}-amide 157 493Naphthalene-1-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-amide 158 494 Isoquinoline-1-carboxylic acid{4-[3-(5-chloro-2,4-dimethoxy-phenyl)- thioureido]-phenyl}-amide 159 494Quinoline-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-amide 160 444N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-nicotinamide161 478 5-Nitro-furan-2-carboxylic acid{4-[3-(5-chloro-2,4-dimethoxy-phenyl)- thioureido]-phenyl}-amidecarbamicacid phenyl ester 162 459{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}- 163 4675-Chloro-furan-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-amide 164 439{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-carbamic acidisobutyl ester 165 397{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-carbamic acidmethyl ester 166 433 Furan-3-carboxylic acid{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]- phenyl}-amide 167 4473-Methyl-furan-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-amide 168 512 5-Bromo-furan-2-carboxylic acid{4-[3-(5-chloro-2,4-dimethoxy-phenyl)- thioureido]-phenyl}-amide 169 5124-Bromo-furan-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-amide 170 433 Furan-2-carboxylic acid{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]- phenyl}-amide 171 467{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-carbamic acidhexyl ester 172 494 Isoquinoline-4-carboxylic acid{4-[3-(5-chloro-2,4-dimethoxy-phenyl)- thioureido]-phenyl}-amide 173 451[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(5-chloro-2,4-dimethoxy-phenyl)- thioureido]-phenyl}-amide 174 4341H-[1,2,3]Triazole-4-carboxylic acid{4-[3-(5-chloro-2,4-dimethoxy-phenyl)- thioureido]-phenyl}-amide 175 5283-Bromo-thiophene-2-carboxylic acid{4-[3-(5-chloro-2,4-dimethoxy-phenyl)- thioureido]-phenyl}-amide 176 399N-{4-[3-(3,5-Dichloro-4-ethoxy-phenyl)-thioureido]-phenyl}-acetamide 177427 N-{4-[3-(4-Butoxy-3,5-dichloro-phenyl)-thioureido]-phenyl}-acetamide178 461N-{4-[3-(4-Benzyloxy-3,5-dichloro-phenyl)-thioureido]-phenyl}-acetamide179 381N-{4-[3-(3-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-acetamide180 530(3-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenylcarbamoyl}-phenyl)-carbamic acid ethyl ester 181 4582-Amino-N-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-benzamide 182 519 Biphenyl-2-carboxylic acid{4-[3-(5-chloro-2,4-dimethoxy-phenyl)- thioureido]-phenyl}-amide 183 4691-(5-Chloro-2,4-dimethoxy-phenyl)-3-[4-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-phenyl]-thiourea 184 487N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}- phthalamicacid 185 473N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2-hydroxy-methyl-benzamide 186 479N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2,3-difluoro-benzamide 187 479N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2,5-difluoro-benzamide 188 479N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2,4-difluoro-benzamide 189 5002-Acetylamino-N-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-benzamide 190 4411-(5-Chloro-2,4-dimethoxy-phenyl)-3-(6-oxo-5,6-dihydro-phenanthridin-2-yl)-thiourea 191 536N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2-methane-sulfonylamino-benzamide 192 497N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2,3,4-trifluoro-benzamide 193 533N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2,3,4,5,6-pentafluoro-benzamide 194 489N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2-methyl-sulfanyl-benzamide 195 431 5-Methyl-furan-2-carboxylic acid{4-[3-(5-chloro-2,4-dimethoxy-phenyl)- ureido]-phenyl}-amide 196 4675-Difluoromethyl-furan-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl)-ureido]-phenyl}-amide 197 472N-{4-[3-(5-Iodo-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-acetamide 204506 1-Hydroxy-naphthalene-2-carboxylic acid{4-[3-(4-acetylamino-phenyl)- thioureido]-2-chloro-phenyl}-amide 205 406N-{4-[3-(3-Chloro-4-morpholin-4-yl-phenyl)-thioureido]-phenyl}-acetamide206 4431-(5-Chloro-2,4-dimethoxy-phenyl)-3-(3-chloro-4-morpholin-4-yl-phenyl)-thiourea 207 3721-(5-Chloro-2,4-dimethoxy-phenyl)-3-(5-chloro-2-methyl-phenyl)-thiourea208 501N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-isophthalamicacid methyl ester 209 487N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-isophthalamicacid 210 5493-Benzyloxy-N-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}benzamide 211 434N-(4-{3-[5-Chloro-2-methoxy-4-(4-nitrilo-butoxy)-phenyl]-thioureido}-phenyl)-acetamide 212 406N-(4-{3-[5-Chloro-2-methoxy-4-(2-nitrilo-ethoxy)-phenyl]-thioureido}-phenyl)-acetamide 213 406N-(4-{3-[5-Chloro-4-methoxy-2-(2-nitrilo-ethoxy)-phenyl]-thioureido}-phenyl)-acetamide 214 411N-(4-{3-[5-Chloro-2-(2-hydroxy-ethoxy)-4-methoxy-phenyl]-thioureido}-phenyl)-acetamide 215 411N-(4-{3-[5-Chloro-4-(2-hydroxy-ethoxy)-2-methoxy-phenyl]-thioureido}-phenyl)-acetamide 216 481{4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro-5-methoxy-phenoxy}-acetic acid tert-butyl ester 217 439{4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro-5-methoxy-phenoxy}-acetic acid methyl ester 218 481{2-[3-(4-Acetylamino-phenyl)-thioureido]-4-chloro-5-methoxy-phenoxy}-acetic acid tert-butyl ester 219 5153-Butoxy-N-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-benzamide 220 505N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2-methane-sulfinyl-benzamide 221 545(3-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenylcarbamoyl}-phenoxy)-acetic acid ethyl ester 222 517(3-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenylcarbamoyl}-218 481{2-[3-(4-Acetylamino-phenyl)-thioureido]-4-chloro-5-methoxy-phenoxy}-acetic acid tert-butyl ester 219 5153-Butoxy-N-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-benzamide 220 505N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2-methane-sulfinyl-benzamide 221 545(3-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenylcarbamoyl}-phenoxy)-acetic acid ethyl ester 222 517(3-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenylcarbamoyl}-phenoxy)-acetic acid 223 367N-{4-[3-(5-Chloro-4-hydroxy-2-methoxy-phenyl)-thioureido]-phenyl}-acetamide 224 444 Pyridine-2-carboxylic acid{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]- phenyl}-amide 225 494Quinoline-4-carboxylic acid{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]- phenyl}-amide 226 436N-{4-[3-(5-Chloro-4-methoxy-2-morpholin-4-yl-phenyl)-thioureido]-phenyl}-acetamide 227 394N-{4-[3-(5-Chloro-2-dimethylamino-4-methoxy-phenyl)-thioureido]-phenyl}-acetamide 228 420N-{4-[3-(5-Chloro-4-methoxy-2-pyrrolidin-1-yl-phenyl)-thioureido]-phenyl}-acetamide 229 434N-{4-[3-(5-Chloro-4-methoxy-2-piperidin-1-yl-phenyl)-thioureido]-phenyl}-acetamide 230 405 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-chloro-4-methyl-phenyl)- thioureido]-phenyl}-amide 231 415N-{4-[3-(3-Chloro-4-methyl-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide232 427N-{4-[3-(3-Chloro-4-methyl-phenyl)-thioureido]-phenyl}-3-methoxy-benzamide233 387 Furan-2-carboxylic acid{4-[3-(3-chloro-4-methyl-phenyl}-thioureido]-phenyl}- amide 234 411N-{4-[3-(3-Chloro-4-methyl-phenyl)-thioureido]-phenyl}-2-methyl-benzamide235 433N-{4-[3-(3-Chloro-4-methyl-phenyl)-thioureido]-phenyl}-2,6-difluoro-benzamide236 398 Pyridine-2-carboxylic acid{4-[3-(3-chloro-4-methyl-phenyl)-thioureido]-phenyl}- amide 237 502[1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[3-chloro-4-(cyclohexyl-methyl-amino)-phenyl]-thioureido}-phenyl)-amide 238 512N-(4-{3-[3-Chloro-4-(cyclohexyl-methyl-amino)-phenyl]-thioureido}-phenyl)-2-fluoro-benzamide 239 404N-{4-[3-(3-Chloro-4-piperidin-1-yl-phenyl)-thioureido]-phenyl}-acetamide240 364N-{4-[3-(3-Chloro-4-dimethylamino-phenyl)-thioureido]-phenyl}-acetamide241 426N-{4-[3-(4-Benzylamino-3-chloro-phenyl)-thioureido]-phenyl}-acetamide242 390N-{4-[3-(3-Chloro-4-pyrrolidin-1-yl-phenyl)-thioureido]-phenyl}-acetamide243 419N-(4-{3-[3-Chloro-4-(4-methyl-piperazin-1-yl)-phenyl]-thioureido}-phenyl)-acetamide 244 469N-{4-[3-(4-Chloro-3-trifluoromethyl-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide 245 422N-{4-[3-(2-Benzylamino-4-methoxy-phenyl)-thioureido]-phenyl}-acetamide246 484 Furan-2-carboxylic acid(4-{3-[3-chloro-4-(cyclohexyl-methyl-amino)-phenyl]-thioureido}-phenyl)-amide 247 508N-(4-{3-[3-Chloro-4-(cyclohexyl-methyl-amino)-phenyl]-thioureido}-phenyl)-2-methyl-benzamide 248 530N-(4-{3-[3-Chloro-4-(cyclohexyl-methyl-amino)-phenyl]-thioureido}-phenyl)-2,6-difluoro-benzamide 249 495 Pyridine-2-carboxylic acid(4-{3-[3-chloro-4-(cyclohexyl-methyl-amino)-phenyl]-thioureido}-phenyl)-amide 250 524N-(4-{3-[3-Chloro-4-(cyclohexyl-methyl-amino)-phenyl]-thioureido}-phenyl)-3-methoxy-benzamide 251 376N-(4-{3-[3-Chloro-4-(2-nitrilo-ethoxy)-phenyl]-thioureido}-phenyl)-acetamide252 393N-{4-[3-(4-sec-Butoxy-3-chloro-phenyl)-thioureido]-phenyl}-acetamide 253501 Acetic acid3-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl-carbamoyl}-phenyl ester 254 459N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido-phenyl}-3-hydroxy-benzamide 255 487 Benzo[1,3]dioxole-4-carboxylic acid{4-[3-(5-chloro-2,4-dimethoxy-phenyl)- thioureido]-phenyl}-amide 256 527N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-3-trifluoro-methoxy-benzamide 257 530N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-3-(2-dimethylamino-ethoxy)-benzamide 258 572N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-3-(2-morpholin-4-yl-ethoxy)-benzamide 259 406N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-2-cyano-phenyl}-acetamide 260 521N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-2,5-dimethoxy-phenyl}-2-fluoro-benzamide 261 441N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-2,5-dimethoxy-phenyl}-acetamide 262 5272-{4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro-phenoxy}-5-chloro-benzenesulfonic acid 263 5622-{4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro-phenoxy}-4,5-dichloro-benzenesulfonic acid 264 527 4-Phenyl-[1,2,3]thiadiazole-5-carboxylicacid{4-[3-(5-chloro-2,4-dimethoxy- phenyl)-thioureido]-phenyl}-amide 265381 N-(4-{3-[3-Chloro-4-(2-hydroxy-ethoxy)-phenyl]-thioureido}-phenyl)-acetamide 266 393N-{4-[3-(4-Butoxy-3-chloro-phenyl)-thioureido]-phenyl}-acetamide 267 446N-(4-{3-[3-Chloro-4-(cyclohexyl-ethyl-amino)-phenyl]-thioureido}-phenyl)-acetamide 268 365N-{4-[3-(3-Chloro-4-ethoxy-phenyl)-thioureido]-phenyl}-acetamide 269 427N-{4-[3-(4-Benzyloxy-3-chloro-phenyl)-thioureido]-phenyl}-acetamide 270317 {4-[(3-Methyl-furan-2-carbonyl)-amino]-phenyl}-carbamicacidtert-butyl ester 271 456N-{4-[3-(2-Benzylamino-5-chloro-4-methoxy-phenyl)-thioureido]-phenyl}-acetamide 272 420N-{4-[3-(3-Chloro-4-dipropylamino-phenyl)-thioureido]-phenyl}-acetamide273 458N-(4-{3-[4-(Allyl-cyclohexyl-amino)-3-chloro-phenyl]-thioureido}-phenyl)-cetamide 274 411N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-2-methoxy-phenyl}-acetamide 275 415N-{2-Chloro-4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-acetamide 276 493 Furan-2-carboxylic acid{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-2,5-dimethoxy-phenyl}-amide 277 486N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-2-cyano-phenyl}-2-fluoro-benzamide 278 495N-{2-Chloro-4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide 279 465 5-Methyl-[1,2,3]thiadiazole-4-carboxylicacid{4-[3-(5-chloro-2,4-dimethoxy- phenyl)-thioureido]-phenyl}-amide 280517 5-Furan-3-yl-[1,2,3]thiadiazole-4-carboxylicacid{4-[3-(5-chloro-2,4- dimethoxy-phenyl)-thioureido]-phenyl}amide 281527 5-Phenyl-[1,2,3]thiadiazole-4-carboxylicacid{4-[3-(5-chloro-2,4-dimethoxy- phenyl)-thioureido]-phenyl}-amide 282458N-(4-{3-[3-Chloro-4-(octahydro-quinolin-1-yl)-phenyl]-thioureido}-phenyl)-acetamide 283 458N-[5-[[[(5-Chloro-2,4-dimethoxyphenyl)amino]thioxomethyl]amino]-2-pyridinyl]-2-methylbenzamide 284 434 Furan-2-carboxylic acid{5-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]- pyridin-2-yl}-amide285 425N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-2-methoxy-5-methyl-phenyl}-acetamide 286 505N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-2-methoxy-5-methyl-phenyl}-2-fluoro-benzamide 287 477 Furan-2-carboxylic acid{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-2-methoxy-5-methyl-phenyl}-amide 288 5174-Furan-3-yl-[1,2,3]thiadiazole-5-carboxylicacid{4-[3-(5-chloro-2,4-dimethoxy- phenyl)-thioureido]-phenyl}-amide 289462N-{5-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-pyridin-2-yl}-2-fluoro-benzamide 290 384N-{4-[3-(4-Methoxy-3-trifluoromethyl-phenyl)-thioureido]-phenyl}-acetamide291 394N-[4-(3-{3-Chloro-4-[(2-hydroxy-ethyl)-methyl-amino]-phenyl}-thioureido)-phenyl]-acetamide 292 485N-{2-Benzoyl-4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-acetamide 293 565N-{2-Benzoyl-4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide 294 537 Furan-2-carboxylic acid{2-benzoyl-4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-amide 295 475N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-3-methyl-phenyl}-2-fluoro-benzamide 296 447 Furan-2-carboxylic acid{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-3-methyl-phenyl}-amide 297 395N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-3-methyl-phenyl}-acetamide 298 435N-[4-(3-{3-Chloro-4-[(3-dimethylamino-propyl)-methyl-amino]-phenyl}-thioureido)-phenyl]-acetamide 299 418N-{4-[3-(3-Chloro-4-cyclohexylamino-phenyl)-thioureido]-phenyl}-acetamide300 421N-[4-(3-{3-Chloro-4-[(2-dimethylamino-ethyl)-methyl-amino]-phenyl}-thioureido)-phenyl]-acetamide 301 5805-[[[(5-Chloro-2,4-dimethoxyphenyl)amino]thioxomethyl]amino]-2-[(2-fluorobenzoyl)amino]-N-phenyl-benzamide 302 552 Furan-2-carboxylic acid{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-2-phenylcarbamoyl-phenyl}-amide 303 491N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-2-methoxy-phenyl}-2-fluoro-benzamide 304 463 Furan-2-carboxylic acid{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-2-methoxy-phenyl}-amide 305 449N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-2-trifluoromethyl-phenyl}-acetamide 306 458 Furan-2-carboxylic acid{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]- 2-cyano-phenyl}-amide307 467 Furan-2-carboxylic acid{2-chloro-4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-amide 308 501 Furan-2-carboxylic acid{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-2-trifluoromethyl-phenyl}-amide 309 395N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-2-methyl-phenyl}-acetamide 310 475N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-2-methyl-phenyl}-2-fluoro-benzamide 311 447 Furan-2-carboxylic acid{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-2-methyl-phenyl}-amide 312 378N-{4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro-phenyl}-acetamide313 408{4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro-phenyl}-carbamic acidethyl ester 314 382N-{5-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-pyridin-2-yl}-acetamide315 509N-(4-{3-[4-(1-Benzyl-piperidin-4-ylamino)-3-chloro-phenyl]-thioureido}-phenyl)-acetamide 316 407N-(4-{3-[3-Chloro-4-(2-dimethylamino-ethylamino)-phenyl]-thioureido}-phenyl)-acetamide 317 408N-[4-(3-{3-Chloro-4-[(2-methoxy-ethyl)-methyl-amino]-phenyl}-thioureido)-phenyl]-acetamide 318 421N-(4-{3-[3-Chloro-4-(3-dimethylamino-propylamino)-phenyl]-thioureido}-phenyl)-acetamide 319 495N-(4-{3-[4-(1-Benzyl-pyrrolidin-3-ylamino)-3-chloro-phenyl]-thioureido}-phenyl)-acetamide 320 483 Furan-2-carboxylic acid{5-chloro-4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-2-hydroxy-phenyl}-amide 321 431N-{5-Chloro-4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-2-hydroxy-phenyl}-acetamide 322 511(5H,11H-Benzo[e]pyrrolo[1,2-a][1,4]diazepin-10-yl)-(2-chloro-4-imidazol-1-yl-phenyl)-methanone 323 451 [1,2,3]Thiadiazole-5-carboxylic acid{4-[3-(5-chloro-2,4-dimethoxy-phenyl)- thioureido]-phenyl}-amide 324 483Furan-2-carboxylic acid{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-naphthalen-1-yl}-amide 325 511N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-naphthalen-1-yl}-2-fluoro-benzamide 326 429N-{5-Chloro-4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-2-methyl-phenyl}-acetamide 327 509N-{5-Chloro-4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-2-methyl-phenyl}-2-fluoro-benzamide 328 481 Furan-2-carboxylic acid{5-chloro-4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-2-methyl-phenyl}-amide 329 431N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-naphthalen-1-yl}-acetamide 330 416 Furan-2-carboxylic acid{4-[3-(3-chloro-4-dimethylamino-phenyl)-thioureido]- phenyl}-amide 331561 Furan-2-carboxylic acid[4-(3-{4-[(1-benzyl-pyrrolidin-3-yl)-methyl-amino]-3-chloro-phenyl}-thioureido)-phenyl]-amide 332 513N-[4-(3-{3-Chloro-4-[methyl-(1-methyl-pyrrolidin-3-yl)-amino]-phenyl}-thioureido)-phenyl]-2-fluoro-benzamide 333 463N-{4-[3-(5-Chloro-2-methoxy-4-methyl-phenyl)-thioureido]-phenyl}-2,6-difluoro-benzamide 334 420N-(4-{3-[3-Chloro-4-(1-methyl-pyrrolidin-3-yloxy)-phenyl]-thioureido}-phenyl)-acetamide 335 434N-(4-{3-[3-Chloro-4-(1-methyl-piperidin-4-yloxy)-phenyl]-thioureido}-phenyl)-acetamide 336 422N-(4-{3-[3-Chloro-4-(3-dimethylamino-propoxy)-phenyl]-thioureido}-phenyl)-acetamide 337 4252-Acetylamino-5-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]- benzoicacid 338 5055-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-2-(2-fluoro-benzoylamino)-benzoic acid 339 4775-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-2-[(furan-2-carbonyl)-amino]-benzoic acid 340 545N-[4-(3-{3-Chloro-4-[methyl-(1-methyl-piperidin-4-yl)-amino]-phenyl}-thioureido)-phenyl]-2,6-difluoro-benzamide 341 503[1,2,3]Thiadiazole-4-carboxylic acid[4-(3-{3-chloro-4-[methyl-(1-methyl-pyrrolidin-3-yl)-amino]-phenyl}-thioureido)-phenyl]-amide 342 443N-{4-[3-(3-Chloro-4-methylsulfanyl-phenyl)-thioureido]-phenyl}-2-methyl-benzamide 343 408N-(4-{3-[3-Chloro-4-(2-dimethylamino-ethoxy)-phenyl]-thioureido}-phenyl)-acetamide 344 499 Furan-2-carboxylic acid[4-(3-{3-chloro-4-[methyl-(1-methyl-piperidin-4-yl)-amino]-phenyl}-thioureido)-phenyl]-amide 345 419N-{4-[3-(3-Chloro-4-cyclohexyloxy-phenyl)-thioureido]-phenyl}-acetamide346 440N-{4-[3-(3-Chloro-4-dimethylamino-phenyl)-thioureido]-phenyl}-2-methyl-benzamide 347 493N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-3-methyl-phenyl}-2,6-difluoro-benzamide 348 462N-{4-[3-(3-Chloro-4-dimethylamino-phenyl)-thioureido]-phenyl}-2,6-difluoro-benzamide 349 531N-[4-(3-{3-Chloro-4-[methyl-(1-methyl-pyrrolidin-3-yl)-amino]-phenyl}-thioureido)-phenyl]-2,6-difluoro-benzamide 350 427 Pyridine-2-carboxylicacid {4-[3-(3-chloro-4-dimethylamino-phenyl)- thioureido]-phenyl}-amide351 430 Pyridine-2-carboxylic acid{4-[3-(3-chloro-4-methylsulfanyl-phenyl)- thioureido]-phenyl}-amide 352428 Pyridine-2-carboxylic acid{4-[3-(5-chloro-2-methoxy-4-methyl-phenyl)- thioureido]-phenyl}-amide353 417 Furan-2-carboxylic acid{4-[3-(5-chloro-2-methoxy-4-methyl-phenyl)- thioureido]-phenyl}-amide354 496 Pyridine-2-carboxylic acid[4-(3-{3-chloro-4-[methyl-(1-methyl-pyrrolidin-3-yl)-amino]-phenyl}-thioureido)- phenyl]-amide 355 495N-{3-Chloro-4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide 356 467 Furan-2-carboxylic acid{3-chloro-4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-amide 357 515N-{4-[3-(3-Chloro-4-cyclohexylsulfanyl-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide 358 449N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-3-trifluoromethyl-phenyl}-acetamide 359 529N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-3-trifluoromethyl-phenyl}-2-fluoro-benzamide 360 421N-{4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro-phenyl}-2-dimethyl-amino-acetamide 361 473 Furan-2-carboxylic acid(4-{3-[3-chloro-4-(2-dimethylamino-acetylamino)-phenyl]-thioureido}-phenyl)-amide 362 501N-(4-{3-[3-Chloro-4-(2-dimethylamino-acetylamino)-phenyl]-thioureido}-phenyl)-2-fluoro-benzamide 363 461N-{4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro-phenyl}-2-piperidin-1-yl-acetamide 364 541N-(4-{3-[3-Chloro-4-(2-piperidin-1-yl-acetylamino)-phenyl]-thioureido}-phenyl)-2-fluoro-benzamide 365 513 Furan-2-carboxylic acid(4-{3-[3-chloro-4-(2-piperidin-1-yl-acetylamino)-phenyl]-thioureido}-phenyl)-amide 366 463N-{4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro-phenyl}-2-morpholin-4-yl-acetamide 367 543N-(4-{3-[3-Chloro-4-(2-morpholin-4-yl-acetylamino)-phenyl]-thioureido}-phenyl)-2-fluoro-benzamide 368 515 Furan-2-carboxylic acid(4-{3-[3-chloro-4-(2-morpholin-4-yl-acetylamino)-phenyl]-thioureido}-phenyl)-amide 369 414N-{4-[3-(3-Chloro-4-methanesulfonylamino-phenyl)-thioureido]-phenyl}-acetamide 370 494N-{4-[3-(3-Chloro-4-methanesulfonylamino-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide 371 466 Furan-2-carboxylic acid{4-[3-(3-chloro-4-methanesulfonylamino-phenyl)-thioureido]-phenyl}-amide 372 481N-{4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro-phenyl}-2-(2-dimethy-lamino-ethylsulfanyl)-acetamide 373 561N-[4-(3-{3-Chloro-4-[2-(2-dimethylamino-ethylsulfanyl)-acetylamino]-phenyl}-thioureido)-phenyl]-2-fluoro-benzamide 374 585N-[4-(3-{4-[(1-Benzyl-pyrrolidin-3-yl)-methyl-amino]-3-chloro-phenyl}-thioureido)-phenyl]-2-methyl-benzamide 375 523N-[4-(3-{3-Chloro-4-[methyl-(1-methyl-piperidin-4-yl)-amino]-phenyl}-thioureido)-phenyl]-2-methyl-benzamide 376 510 Pyridine-2-carboxylicacid [4-(3-{3-chloro-4-[methyl-(1-methyl-piperidin-4-yl)-amino]-phenyl}-thioureido)-phenyl]-amide 377 347N-{4-[3-(3-Chloro-4-vinyl-phenyl)-thioureido]-phenyl}-acetamide 378 441Furan-2-carboxylic acid {4-[3-(4-chloro-3-trifluoromethyl-phenyl)-thioureido]-phenyl)-amide 379 452 Pyridine-2-carboxylic acid{4-[3-(4-chloro-3-trifluoromethyl-phenyl)- thioureido]-phenyl}-amide 380487 N-{4-[3-(4-Chloro-3-trifluoromethyl-phenyl)-thioureido]-phenyl}-2,6-difluoro-benzamide 381 486N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-3-cyano-phenyl}-2-fluoro-benzamide 382 458 Furan-2-carboxylic acid{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-3- cyano-phenyl}-amide383 406N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-3-cyano-phenyl}-acetamide 384 395N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-2-methyl-isothioureido]-phenyl}-acetamide 385 396N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-2-methyl-isothioureido]-phenyl}-acetamide 386 461N-{4-[3-(3-Chloro-4-ethylsulfanyl-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide 387 489N-{4-[3-(4-Butylsulfanyl-3-chloro-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide 388 411N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-3-methoxy-phenyl}-acetamide 389 491N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-3-methoxy-phenyl}-2-fluoro-benzamide 390 463 Furan-2-carboxylic acid{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-3-methoxy-phenyl}-amide 391 531 [1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[3-chloro-4-(2-piperidin-1-yl-acetyl-amino)-phenyl]-thioureido}-phenyl)-amide 392 481N-{4-[3-(3-Chloro-4-methanesulfinyl-phenyl)-thioureido]-phenyl}-2,6-difluoro-benzamide 393 497N-{4-[3-(3-Chloro-4-methanesulfonyl-phenyl)-thioureido]-phenyl}-2,6-difluoro-benzamide 394 459N-{4-[3-(5-Chloro-2-methoxy-4-methyl-phenyl)-thioureido]-2-methyl-phenyl}-2-fluoro-benzamide 395 429N-{4-[3-(3-Chloro-4-methyl-phenyl)-thioureido]-2-methyl-phenyl}-2-fluoro-benzamide 396 533 Furan-2-carboxylic acid[4-(3-{3-chloro-4-[2-(2-dimethylamino-ethylsulfanyl)-acetylamino]-phenyl}-thioureido)-phenyl]-amide 397 458N-{4-[3-(4-Acetylamino-3-chloro-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide 398 460[2-Chloro-4-(3-{4-[(furan-2-carbonyl)-amino]-phenyl}-thioureido)-phenyl]-carbamic acid ethyl ester 399 488(2-Chloro-4-{3-[4-(2-fluoro-benzoylamino)-phenyl]-thioureido}-phenyl)-carbamic acid ethyl ester 400 440N-{4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro-phenyl}-benzamide401 520N-{4-[({[4-(Benzoylamino)-3-chloro-phenyl]-amino}-thioxomethyl)-amino]-phenyl}-2-fluoro-benzamide 402 529N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-2-trifluoromethyl-phenyl}-2-fluoro-benzamide 403 492 Furan-2-carboxylic acid{4-[3-(4-benzoylamino-3-chloro-phenyl)-thioureido]- phenyl}-amide 404416N-{4-[3-(4-Amino-3-chloro-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide405 479 N-{4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro-phenyl}-2-thiomorpholin-4-yl-acetamide 406 531 Furan-2-carboxylic acid(4-{3-[3-chloro-4-(2-thiomorpholin-4-yl-acetylamino)-phenyl]-thioureido}-phenyl)-amide 407 559N-(4-{3-[3-Chloro-4-(2-thiomorpholin-4-yl-acetylamino)-phenyl]-thioureido}-phenyl)-2-fluoro-benzamide 408 461N-{4-[3-(3-Chloro-4-methylsulfanyl-phenyl)-thioureido]-2-methyl-phenyl}-2-fluoro-benzamide 409 430 Furan-2-carboxylic acid{4-[3-(4-acetylamino-3-chloro-phenyl)-thioureido]- phenyl}-amide 410 477N-{4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro-phenyl}-2-dipropylamino-acetamide 411 529 Furan-2-carboxylic acid(4-{3-[3-chloro-4-(2-dipropylamino-acetylamino)-phenyl]-thioureido}-phenyl)-amide 412 449N-{4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro-phenyl}-2-diethyl-amino-acetamide 413 501 Furan-2-carboxylic acid(4-{3-[3-chloro-4-(2-diethylamino-acetylamino)-phenyl]-thioureido}-phenyl)-amide 414 529N-(4-{3-[3-Chloro-4-(2-diethylamino-acetylamino)-phenyl]-thioureido}-phenyl)-2-fluoro-benzamide 415 447N-{4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro-phenyl}-2-pyrrolidin-1-yl-acetamide 416 499 Furan-2-carboxylic acid(4-{3-[3-chloro-4-(2-pyrrolidin-1-yl-acetylamino)-phenyl]-thioureido}-phenyl)-amide 417 527N-(4-{3-[3-Chloro-4-(2-pyrrolidin-1-yl-acetylamino)-phenyl]-thioureido}-phenyl)-2-fluoro-benzamide 418 475N-{4-[3-(5-Chloro-2-methoxy-4-methyl-phenyl)-thioureido]-3-methoxy-phenyl}-2-fluoro-benzamide 419 445N-{4-[3-(3-Chloro-4-methyl-phenyl)-thioureido]-3-methoxy-phenyl}-2-fluoro-benzamide 420 477N-{4-[3-(3-Chloro-4-methylsulfanyl-phenyl)-thioureido]-3-methoxy-phenyl}-2-fluoro-benzamide 421 388 Furan-2-carboxylic acid{4-[3-(4-amino-3-chloro-phenyl)-thioureido]-phenyl}- amide 422 527Furan-2-carboxylic acid(4-{3-[4-(2-azepan-1-yl-acetylamino)-3-chloro-phenyl]-thioureido}-phenyl)-amide 423 555N-(4-{3-[4-(2-Azepan-1-yl-acetylamino)-3-chloro-phenyl]-thioureido}-phenyl)-2-fluoro-benzamide 424 527 Furan-2-carboxylic acid[4-(3-{3-chloro-4-[2-(2-methyl-piperidin-1-yl)-acetyl-amino]-phenyl}-thioureido)-phenyl]-amide 425 555N-[4-(3-{3-Chloro-4-[2-(2-methyl-piperidin-1-yl)-acetylamino]-phenyl}-thioureido)-phenyl]-2-fluoro-benzamide 426 339 Furan-2-carboxylic acid[4-(3-pyridin-2-yl-thioureido)-phenyl]-amide 427 339 Furan-2-carboxylicacid [4-(3-pyridin-4-yl-thioureido)-phenyl]-amide 428 3672-Fluoro-N-[4-(3-pyridin-3-yl-thioureido)-phenyl]-benzamide 429 339Furan-2-carboxylic acid [4-(3-pyridin-3-yl-thioureido)-phenyl]-amide 430353 Furan-2-carboxylic acid{4-[3-(3-amino-phenyl)-thioureido]-phenyl}-amide 431 406Furan-2-carboxylic acid{4-[3-(3-trifluoromethyl-phenyl)-thioureido]-phenyl}- amide 432 3802-Fluoro-N-[4-(3-m-tolyl-thioureido)-phenyl]-benzamide 433 4342-Fluoro-N-{4-[3-(3-trifluoromethyl-phenyl)-thioureido]-phenyl}-benzamide 434 381N-{4-[3-(3-Amino-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide 435 388Furan-2-carboxylic acid {4-[3-(3-amino-5-chloro-phenyl)-thioureido]-phenyl}-amide 436 352 Furan-2-carboxylic acid[4-(3-m-tolyl-thioureido)-phenyl]-amide 437 416N-{4-[3-(2-Amino-5-chloro-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide438 571(2-Chloro-4-{3-[4-(2-fluoro-benzoylamino)-phenyl]-thioureido}-phenyl)-carbamic acid 2-piperidin-1-yl-ethyl ester 439 543[2-Chloro-4-(3-{4-[(furan-2-carbonyl)-amino]-phenyl}-thioureido)-phenyl]-carbamic acid 2-piperidin-1-yl-ethyl ester 440 388 Furan-2-carboxylicacid {4-[3-(2-amino-5-chloro-phenyl)-thioureido]- phenyl}-amide 441 363Furan-2-carboxylic acid {4-[3-(3-cyano-phenyl)-thioureido]-phenyl}-amide 442 416N-{4-[3-(3-Amino-5-chloro-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide443 367 2-Fluoro-N-[4-(3-pyridin-2-yl-thioureido)-phenyl]-benzamide 444367 2-Fluoro-N-[4-(3-pyridin-4-yl-thioureido)-phenyl]-benzamide 445 374Furan-2-carboxylic acid{4-[3-(6-chloro-pyridin-3-yl)-thioureido]-phenyl}- amide 446 388Furan-2-carboxylic acid{4-[3-(2-amino-3-chloro-phenyl)-thioureido]-phenyl}- amide 447 396Furan-2-carboxylic acid{4-[3-(3-hydrazinocarbonyl-phenyl)-thioureido]-phenyl}- amide 448 4102-Fluoro-N-(4-{3-[3-(1-hydroxy-ethyl)-phenyl]-thioureido}-phenyl)-benzamide449 414 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-hydrazinocarbonyl-phenyl)- thioureido]-phenyl}-amide 450 399[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-isopropyl-phenyl)-thioureido]- phenyl}-amide 451 380Furan-2-carboxylic acid {4-[3-(3-isopropyl-phenyl)-thioureido]-phenyl}-amide 452 4092-Fluoro-N-{4-[3-(3-isopropyl-phenyl)-thioureido]-phenyl}-benzamide 453381 [1,2,3]Thiadiazole-4-carboxylicacid{4-[3-(3-cyano-phenyl)-thioureido]- phenyl}-amide 454 410N-{4-[3-(3-Dimethylamino-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide455 381 Furan-2-carboxylic acid{4-[3-(3-dimethylamino-phenyl)-thioureido]-phenyl}- amide 456 370[1,2,3]Thiadiazole-4-carboxylic acid[4-(3-m-tolyl-thioureido)-phenyl]-amide 457 424[1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-trifluoromethyl-phenyl)-thioureido]-phenyl}-amide 458 479N-{3-Chloro-4-[3-(5-chloro-2-methoxy-4-methyl-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide 459 449N-{3-Chloro-4-[3-(3-chloro-4-methyl-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide 460 481N-{3-chloro-4-[3-(3-chloro-4-methylsulfanyl-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide 461 391N-{4-[3-(3-Cyano-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide 462 395Furan-2-carboxylic acid{4-[3-(3-acetylamino-phenyl)-thioureido]-phenyl}- amide 463 4242-Fluoro-N-{4-[3-(3-hydrazinocarbonyl-phenyl)-thioureido]-phenyl}-benzamide464 400 [1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[3-(1-hydroxy-ethyl)-phenyl]- thioureido}-phenyl)-amide 465 434N-{4-[3-(2-Amino-3-chloro-phenyl)-thioureido]-phenyl}-2,6-difluoro-benzamide466 406 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-amino-5-chloro-phenyl)- thioureido]-phenyl}-amide 467 398Furan-2-carboxylic acid{4-[3-(3,5-dimethoxy-phenyl)-thioureido]-phenyl}- amide 468 416[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3,5-dimethoxy-phenyl)-thioureido]- phenyl}-amide 469 4545-(3-{4-[(Furan-2-carbonyl)-amino]-phenyl}-thioureido)-isophthalic aciddimethyl ester 470 434 Isoxazole-5-carboxylic acid{4-[3-(5-chloro-2,4-dimethoxy-phenyl)- thioureido]-phenyl}-amide 471 392[1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(6-chloro-pyridin-3-yl)-thioureido]-phenyl}-amide 472 382 Furan-2-carboxylic acid(4-{3-[3-(1-hydroxy-ethyl)-phenyl]-thioureido}- phenyl)-amide 473 368Furan-2-carboxylic acid{4-[3-(3-methoxy-phenyl)-thioureido]-phenyl}-amide 474 354Furan-2-carboxylic acid{4-[3-(3-hydroxy-phenyl)-thioureido]-phenyl}-amide 475 3822-Fluoro-N-{4-[3-(3-hydroxy-phenyl)-thioureido]-phenyl}-benzamide 4763962-Fluoro-N-{4-[3-(3-hydroxymethyl-phenyl)-thioureido]-phenyl}-benzamide477 423N-{4-[3-(3-Acetylamino-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide478 413 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-acetylamino-phenyl)-thioureido]- phenyl}-amide 479 400[1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-dimethylamino-phenyl)-thioureido]-phenyl}-amide 480 340 Furan-2-carboxylic acid[4-(3-pyrimidin-4-yl-thioureido)-phenyl]-amide 481 378Furan-2-carboxylic acid{4-[3-(1H-indazol-5-yl)-thioureido]-phenyl}-amide 482 395Furan-2-carboxylic acid[4-(3-benzothiazol-5-yl-thioureido)-phenyl]-amide 483 4062-Fluoro-N-{4-[3-(1H-indazol-5-yl)-thioureido]-phenyl}-benzamide 484 424N-[4-(3-Benzothiazol-5-yl-thioureido)-phenyl]-2-fluoro-benzamide 485 4735-(3-{4-[([1,2,3]Thiadiazole-4-carbonyl)-amino]-phenyl}-thioureido)-isophthalic acid dimethyl ester 486 442 Furan-2-carboxylic acid(4-{3-[4-(1-azido-ethyl)-3-chloro-phenyl]- thioureido}-phenyl)-amide 487396 2-Fluoro-N-{4-[3-(3-methoxy-phenyl)-thioureido]-phenyl}-benzamide488 368 Furan-2-carboxylic acid{4-[3-(3-hydroxymethyl-phenyl)-thioureido]-phenyl}- amide 489 416Furan-2-carboxylic acid{4-[3-(5-chloro-2-dimethylamino-phenyl)-thioureido]- phenyl}-amide 490444N-{4-[3-(5-Chloro-2-dimethylamino-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide 491 506[3-Chloro-5-(3-{4-[([1,2,3]thiadiazole-4-carbonyl)-amino]-phenyl}-thioureido)-phenyl]-carbamic acid tert-butyl ester 492 470N-(4-{3-[4-(1-Azido-ethyl)-3-chloro-phenyl]-thioureido}-phenyl)-2-fluoro-benzamide 493 337 Furan-2-carboxylic acid[4-(1H-thiazolo[5,4-b]pyridin-2-ylideneamino)- phenyl]-amide 494 378Furan-2-carboxylic acid{4-[3-(1H-benzoimidazol-5-yl)-thioureido]-phenyl}-amide 495 392Furan-2-carboxylic acid{4-[3-(2-methyl-1H-benzoimidazol-5-yl)-thioureido]- phenyl}-amide 496406N-{4-[3-(1H-Benzoimidazol-5-yl)-thioureido]-phenyl}-2-fluoro-benzamide497 4202-Fluoro-N-{4-[3-(2-methyl-1H-benzoimidazol-5-yl)-thioureido]-phenyl}-benzamide 498 452 [1,2,3]Thiadiazole-4-carboxylic acid{5-[3-(5-chloro-2,4-dimethoxy-phenyl)- thioureido]-pyridin-2-yl}-amide499 445 Pyridine-2-carboxylic acid{5-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]- pyridin-2-yl}-amide500 434 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(5-chloro-2-dimethylamino-phenyl)- thioureido]-phenyl}-amide 501484 [1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[4-(2-amino-pyrimidin-4-yl)-3-chloro-phenyl]-thioureido}-phenyl)-amide 502 494N-(4-{3-[4-(2-Amino-pyrimidin-4-yl)-3-chloro-phenyl]-thioureido}-phenyl)-2-fluoro-benzamide 503 434 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-chloro-2-dimethylamino-phenyl)- thioureido]-phenyl}-amide 504462N-{4-[3-(3-Chloro-2-dimethylamino-phenyl)-thioureido]-phenyl}-2,6-difluoro-benzamide 505 416 Furan-2-carboxylic acid{4-[3-(3-chloro-2-dimethylamino-phenyl)-thioureido]- phenyl}-amide 506445 Pyridine-2-carboxylic acid{6-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]- pyridin-3-yl}-amide507 462N-{6-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-pyridin-3-yl}-2-fluoro-benzamide 508 482 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-iodo-phenyl)-thioureido]-phenyl}- amide 509 413[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-tert-butyl-phenyl)-thioureido]- phenyl}-amide 510 387Furan-2-carboxylic acid{4-[3-(3-chloro-benzyl)-thioureido]-phenyl}-amide 511 415N-{4-[3-(3-Chloro-benzyl)-thioureido]-phenyl}-2-fluoro-benzamide 512 434Furan-2-carboxylic acid{6-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]- pyridin-3-yl}-amide513 435 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-bromo-phenyl)-thioureido]- phenyl}-amide 514 452[1,2,3]Thiadiazole-4-carboxylic acid{6-[3-(5-chloro-2,4-dimethoxy-phenyl)- thioureido]-pyridin-3-yl}-amide515 426 [1,2,3]Thiadiazole-4-carboxylic acid{5-[3-(3,5-dichloro-phenyl)-thioureido]- pyridin-2-yl}-amide 516 474Furan-2-carboxylic acid{4-[3-(3,5-bis-trifluoromethyl-phenyl)-thioureido]- phenyl}-amide 517502N-{4-[3-(3,5-Bis-trifluoromethyl-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide 518 450N-{4-[3-(4-Amino-3,5-dichloro-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide 519 539N-{4-[3-(4-Amino-3,5-dibromo-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide 520 392 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(5-chloro-pyridin-3-yl)-thioureido]- phenyl}-amide 521 529[1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-amino-3,5-dibromo-phenyl)-thioureido]-phenyl}-amide 522 434 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-chloro-5-dimethylamino-phenyl)- thioureido]-phenyl}-amide 523444N-{4-[3-(3-Chloro-5-dimethylamino-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide 524 416 Furan-2-carboxylic acid{4-[3-(3-chloro-5-dimethylamino-phenyl)-thioureido]- phenyl}-amide 525436 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(5-bromo-pyridin-3-yl)-thioureido]- phenyl}-amide 526 379Furan-2-carboxylic acid{4-[3-(1H-benzotriazol-5-yl)-thioureido]-phenyl}-amide 527 425N-{4-[3-(1H-Benzotriazol-5-yl)-thioureido]-phenyl}-2,6-difluoro-benzamide528 388N-[4-({[2-(3-Chloro-phenyl)-hydrazino]-thioxomethyl}-amino)-phenyl]-furan-2-carboxamide 529 416N-[4-({[2-(3-Chloro-phenyl)-hydrazino]-thioxomethyl}-amino)-phenyl]-2-fluoro-benzamide 530 456 Furan-2-carboxylic acid{4-[3-(2-amino-3-chloro-5-trifluoromethyl-phenyl)-thioureido]-phenyl}-amide 531 513N-{4-[3-(3-Bromo-5-trifluoromethyl-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide 532 503 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-bromo-5-trifluoromethyl-phenyl)- thioureido]-phenyl}-amide 533374 {4-[(Furan-2-carbonyl)-amino]-phenyl}-thiocarbamic acidO-(3-chloro-phenyl) ester 534 474 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(2-amino-3-chloro-5-trifluoro-methyl-phenyl)-thioureido]-phenyl}-amide 535 508[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-piperidin-1-yl-5-trifluoromethyl-phenyl)-thioureido]-phenyl}-amide 536 380N-[4-(3-Benzyl-thioureido)-phenyl]-2-fluoro-benzamide 537 439[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3,4-dichloro-benzyl)-thioureido]- phenyl}-amide 538 449N-{4-[3-(3,4-Dichloro-benzyl)-thioureido]-phenyl}-2-fluoro-benzamide 539370 [1,2,3]Thiadiazole-4-carboxylic acid[4-(3-benzyl-thioureido)-phenyl]-amide 540 424N-[4-(3-Benzo[1,3]dioxol-5-ylmethyl-thioureido)-phenyl]-2-fluoro-benzamide541 414 [1,2,3]Thiadiazole-4-carboxylic acid[4-(3-benzo[1,3]dioxol-5-ylmethyl- thioureido)-phenyl]-amide 542 506[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3,5-bis-trifluoromethyl-benzyl)- thioureido]-phenyl}-amide 543516N-{4-[3-(3,5-Bis-trifluoromethyl-benzyl)-thioureido]-phenyl}-2-fluoro-benzamide544 352 Furan-2-carboxylic acid [4-(3-benzyl-thioureido)-phenyl]-amide545 421 Furan-2-carboxylic acid{4-[3-(3,4-dichloro-benzyl)-thioureido]-phenyl}-amide 546 396Furan-2-carboxylic acid[4-(3-benzo[1,3]dioxol-5-ylmethyl-thioureido)-phenyl]- amide 547 488Furan-2-carboxylic acid{4-[3-(3,5-bis-trifluoromethyl-benzyl)-thioureido]- phenyl}-amide 548503 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(4-bromo-3-trifluoromethyl-phenyl)- thioureido]-phenyl}-amide 549529N-{4-[3-(3-Bromo-4-trifluoromethoxy-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide 550 519 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-bromo-4-trifluoromethoxy- phenyl)-thioureido]-phenyl}-amide 551473 Furan-2-carboxylic acid{4-[3-(3-chloro-4-trifluoromethylsulfanyl-phenyl)-thioureido]-phenyl}-amide 552 4122-Fluoro-N-(4-{3-[2-(3-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-benzamide553 4122-Fluoro-N-(4-{3-[2-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-benzamide554 402 [1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(3-fluoro-phenyl)-ethyl]- thioureido}-phenyl)-amide 555 402[1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-amide 556 495 [1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[3-(2-methyl-butyl)-5-trifluoro-methyl-phenyl]-thioureido}-phenyl)-amide 557 481[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-isobutyl-5-trifluoromethyl-phenyl)- thioureido]-phenyl}-amide558 523 [1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[3-(4-methyl-piperazin-1-yl)-5-trifluoro-methyl-phenyl]-thioureido}-phenyl)-amide 559 510[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-morpholin-4-yl-5-trifluoromethyl-phenyl)-thioureido]-phenyl}-amide 560 494[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-pyrrolidin-1-yl-5-trifluoromethyl-phenyl)-thioureido]-phenyl}-amide 561 384 Furan-2-carboxylic acid(4-{3-[2-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)- amide 562 419[1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3-chloro-phenyl)-ethyl]-thioureido}-phenyl)-amide 563 429N-(4-{3-[2-(3-Chloro-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide564 401 Furan-2-carboxylic acid(4-{3-[2-(3-chloro-phenyl)-ethyl]-thioureido}-phenyl)- amide 565 402[1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}- phenyl)-amide 566 5042-Fluoro-N-{4-[3-(3-pyrrolidin-1-yl-5-trifluoromethyl-phenyl)-thioureido]-phenyl}-benzamide 567 477N-{4-[3-(3-Dimethylamino-5-trifluoromethyl-phenyl)-thioureido]-phenyl}-2-fluoro-Benzamide 568 5202-Fluoro-N-{4-[3-(3-morpholin-4-yl-5-trifluoromethyl-phenyl)-thioureido]-phenyl}-benzamide 569 5332-Fluoro-N-(4-{3-[3-(4-methyl-piperazin-1-yl)-5-trifluoromethyl-phenyl]-thioureido}-phenyl)-benzamide 570 5182-Fluoro-N-{4-[3-(3-piperidin-1-yl-5-trifluoromethyl-phenyl)-thioureido]-phenyl}-benzamide 571 468 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-dimethylamino-5-trifluoromethyl-phenyl)-thioureido]-phenyl}-amide 572 405[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-chloro-benzyl)-thioureido]-phenyl}- amide 573 384Furan-2-carboxylic acid(4-{3-[2-(3-fluoro-phenyl)-ethyl]-thioureido}-phenyl)- amide 574 366Furan-2-carboxylic acid [4-(3-phenethyl-thioureido)-phenyl]-amide 575384 [1,2,3]Thiadiazole-4-carboxylic acid[4-(3-phenethyl-thioureido)-phenyl]-amide 576 3942-Fluoro-N-[4-(3-phenethyl-thioureido)-phenyl]-benzamide 577 5052-Fluoro-N-(4-{3-[3-(2-methyl-butyl)-5-trifluoromethyl-phenyl]-thioureido}-phenyl)-benzamide 578 4912-Fluoro-N-{4-[3-(3-isobutyl-5-trifluoromethyl-phenyl)-thioureido]-phenyl}-benzamide 579 388 Furan-2-carboxylic acid{4-[3-(3,5-difluoro-benzyl)-thioureido]-phenyl}-amide 580 416N-{4-[3-(3,5-Difluoro-benzyl)-thioureido]-phenyl}-2-fluoro-benzamide 581406 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3,5-difluoro-benzyl)-thioureido]- phenyl}-amide 582 421Furan-2-carboxylic acid{4-[3-(3,5-dichloro-benzyl)-thioureido]-phenyl}-amide 583 449N-{4-[3-(3,5-Dichloro-benzyl)-thioureido]-phenyl}-2-fluoro-benzamide 584439 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3,5-dichloro-benzyl)-thioureido]- phenyl}-amide 585 438Furan-2-carboxylic acid{4-[3-(3-fluoro-5-trifluoromethyl-benzyl)-thioureido]- phenyl}-amide 5864662-Fluoro-N-{4-[3-(3-fluoro-5-trifluoromethyl-benzyl)-thioureido]-phenyl}-benzamide 587 456 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-fluoro-5-trifluoromethyl- benzyl)-thioureido]-phenyl}-amide 588384 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(1-phenyl-ethyl)-thioureido]-phenyl}- amide 589 3942-Fluoro-N-{4-[3-(1-phenyl-ethyl)-thioureido]-phenyl}-benzamide 590 366Furan-2-carboxylic acid {4-[3-(1-phenyl-ethyl)-thioureido]-phenyl}-amide591 4122-Fluoro-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-benzamide592 384 Furan-2-carboxylic acid(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)- amide 593 413N-{4-[3-(1-tert-Butyl-1H-imidazol-2-yl)-thioureido]-phenyl}-2-fluoro-benzamide 594 510 [1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[3-(isobutyl-methyl-amino)-5-trifluoromethyl-phenyl]-thioureido}-phenyl)-amide 595 510[1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[3-(3-hydroxy-pyrrolidin-1-yl)-5-trifluoromethyl-phenyl]-thioureido}-phenyl)-amide 596 5202-Fluoro-N-(4-{3-[3-(isobutyl-methyl-amino)-5-trifluoromethyl-phenyl]-thioureido}-phenyl)-benzamide 597 510 [1,2,3]Thiadiazole-4-carboxylicacid (4-{3-[3-(butyl-methyl-amino)-5-trifluoromethyl-phenyl]-thioureido}-phenyl)-amide 598 520N-(4-{3-[3-(Butyl-methyl-amino)-5-trifluoromethyl-phenyl]-thioureido}-phenyl)-2-fluoro-benzamide 599 520 [1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-thioureido}-phenyl)-amide 600 442[1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-fluoro-3-trifluoromethyl-phenyl)-thioureido]-phenyl}-amide 601 522[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(4-piperidin-1-yl-3-trifluoromethyl-benzyl)-thioureido]-phenyl}-amide 602 482[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(4-dimethylamino-3-trifluoromethyl-benzyl)-thioureido]-phenyl}-amide 603 381 Furan-2-carboxylic acid(4-{3-[2-(4-amino-phenyl)-ethyl]-thioureido}- phenyl)-amide 604 445Furan-2-carboxylic acid (4-{3-[2-(4-bromo-phenyl)-ethyl]-thioureido}-phenyl)-amide 605 380 Furan-2-carboxylic acid{4-[3-(2-p-tolyl-ethyl)-thioureido]-phenyl}-amide 606 463[1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(4-bromo-phenyl)-ethyl]-thioureido}-phenyl)-amide 607 396 Furan-2-carboxylic acid(4-{3-[2-(3-methoxy-phenyl)-ethyl]-thioureido}-phenyl)- amide 608 403[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(1-tert-butyl-1H-imidazol-2-yl)- thioureido]-phenyl}-amide 609 384Furan-2-carboxylic acid{4-[3-(1-tert-butyl-1H-imidazol-2-yl)-thioureido]-phenyl}- amide 610 492N-{4-[3-(4-Dimethylamino-3-trifluoromethyl-benzyl)-thioureido]-phenyl}-2-fluoro-benzamide 611 427 Furan-2-carboxylic acid(4-{3-[2-(3,4-dimethoxy-phenyl)-ethyl]-thioureido}- phenyl)-amide 612380 Furan-2-carboxylic acid{4-[3-(3-phenyl-propyl)-thioureido]-phenyl}-amide 613 399[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-phenyl-propyl)-thioureido]-phenyl}- amide 614 502Furan-2-carboxylic acid(4-{3-[2-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-thioureido}-phenyl)-amide 615 550 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(4-iodo-3-trifluoromethyl-phenyl)- thioureido]-phenyl}-amide 6165322-Fluoro-N-{4-[3-(4-piperidin-1-yl-3-trifluoromethyl-benzyl)-thioureido]-phenyl}-benzamide 617 537 [1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[4-(4-methyl-piperazin-1-yl)-3-trifluoromethyl-benzyl]-thioureido}-phenyl)-amide 618 482[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-dimethylamino-5-trifluoromethyl-benzyl)-thioureido]-phenyl}amide 619 488 Furan-2-carboxylic acid{4-[3-(3,5-bis-trifluoromethyl-phenyl)-thioureido- methyl]-phenyl}-amide620 421 Furan-2-carboxylic acid{4-[3-(3,5-dichloro-phenyl)-thioureidomethyl]- phenyl}-amide 621 421Furan-2-carboxylic acid {4-[3-(3,4-dichloro-phenyl)-thioureidomethyl]-phenyl}-amide 622 455 Furan-2-carboxylic acid{4-[3-(4-chloro-3-trifluoromethyl-phenyl)-thioureido-methyl]-phenyl}-amide 623 4662-Fluoro-N-{4-[3-(4-fluoro-3-trifluoromethyl-benzyl)-thioureido]-phenyl}-benzamide 624 456 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(4-fluoro-3-trifluoromethyl-benzyl)- thioureido]-phenyl}-amide 625410 2-Fluoro-N-{4-[3-(2-phenoxy-ethyl)-thioureido]-phenyl}-benzamide 626382 Furan-2-carboxylic acid{4-[3-(2-phenoxy-ethyl)-thioureido]-phenyl}-amide 627 400[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(2-phenoxy-ethyl)-thioureido]- phenyl}-amide 628 4092-Fluoro-N-{4-[3-(3-phenyl-propyl)-thioureido]-phenyl}-benzamide 629 425[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(5-trifluoromethyl-pyridin-3-yl)- thioureido]-phenyl}-amide 630439 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3,4-dichloro-phenyl)-thioureido- methyl]-phenyl}-amide 631 473[1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-chloro-3-trifluoromethyl-phenyl)-thioureidomethyl]-phenyl}-amide 632 3812-Fluoro-N-[4-(3-pyridin-3-ylmethyl-thioureido)-phenyl]-benzamide 633353 Furan-2-carboxylic acid[4-(3-pyridin-3-ylmethyl-thioureido)-phenyl]-amide 634 371[1,2,3]Thiadiazole-4-carboxylic acid[4-(3-pyridin-3-ylmethyl-thioureido)- phenyl]-amide 635 439[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3,5-dichloro-phenyl)-thioureido- methyl]-phenyl}-amide 636 492N-{4-[3-(3-Dimethylamino-5-trifluoromethyl-benzyl)-thioureido]-phenyl}-2-fluoro-benzamide 637 415 [1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(3-methoxy-phenyl)-ethyl]- thioureido}-phenyl)-amide 638 399[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(2-p-tolyl-ethyl)-thioureido]- phenyl}-amide 639 445[1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(3,4-dimethoxy-phenyl)-ethyl]- thioureido}-phenyl)-amide 640506 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3,5-bis-trifluoromethyl-phenyl)- thioureidomethyl]-phenyl}-amide641 516N-{4-[3-(3,5-Bis-trifluoromethyl-phenyl)-thioureidomethyl]-phenyl}-2-fluoro-benzamide 642 449N-{4-[3-(3,5-Dichloro-phenyl)-thioureidomethyl]-phenyl}-2-fluoro-benzamide643 449N-{4-[3-(3,4-Dichloro-phenyl)-thioureidomethyl]-phenyl}-2-fluoro-benzamide644 448 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-acetylamino-5-chloro-phenyl)- thioureido]-phenyl}-amide 645 453[1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(3,4-dichloro-phenyl)-ethyl]- thioureido}-phenyl)-amide 646 413[1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(1-methyl-3-phenyl-propyl)-thioureido]-phenyl}-amide 647 463 [1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[1-(4-bromo-phenyl)-ethyl]- thioureido}-phenyl)-amide 648 413[1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-phenyl-butyl)-thioureido]-phenyl}-amide 649 397 [1,2,3]Thiadiazole-4-carboxylic acid[4-(3-indan-1-yl-thioureido)-phenyl]-amide 650 400[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(2-methoxy-benzyl)-thioureido]- phenyl}-amide 651 415[1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(2-methoxy-phenyl)-ethyl]-thioureido}-phenyl)-amide 652 415 [1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(4-methoxy-phenyl)-ethyl]- thioureido}-phenyl)-amide 653 506N-(4-{3-[2-(3-Dimethylamino-5-trifluoromethyl-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide 654 510 [1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[3-(3-dimethylamino-propyl)-5-trifluoromethyl-phenyl]-thioureido}-phenyl)-amide 655 417[1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(2-phenylsulfanyl-ethyl)-thioureido]-phenyl}-amide 656 4272-Fluoro-N-{4-[3-(2-phenylsulfanyl-ethyl)-thioureido]-phenyl}-benzamide657 399 Furan-2-carboxylic acid{4-[3-(2-phenylsulfanyl-ethyl)-thioureido]-phenyl}- amide 658 3812-Fluoro-N-[4-(3-pyridin-4-ylmethyl-thioureido)-phenyl]-benzamide 659353 Furan-2-carboxylic acid[4-(3-pyridin-4-ylmethyl-thioureido)-phenyl]-amide 660 371[1,2,3]Thiadiazole-4-carboxylic acid[4-(3-pyridin-4-ylmethyl-thioureido)- phenyl]-amide 661 5062-Fluoro-N-{4-[3-(3-iodo-benzyl)-thioureido]-phenyl}-benzamide 662 478Furan-2-carboxylic acid {4-[3-(3-iodo-benzyl)-thioureido]-phenyl}-amide663 496 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-iodo-benzyl)-thioureido]-phenyl}- amide 664 479N-(4-{3-[2-(3,5-Dichloro-phenoxy)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide 665 451 Furan-2-carboxylic acid(4-{3-[2-(3,5-dichloro-phenoxy)-ethyl]-thioureido}- phenyl)-amide 666445N-(4-{3-[2-(3-Chloro-phenoxy)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide667 417 Furan-2-carboxylic acid(4-{3-[2-(3-chloro-phenoxy)-ethyl]-thioureido}-phenyl)- amide 668 435[1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3-chloro-phenoxy)-ethyl]-thioureido}-phenyl)-amide 669 4662-Fluoro-N-{4-[3-(2-fluoro-5-trifluoromethyl-benzyl)-thioureido]-phenyl}-benzamide 670 438 Furan-2-carboxylic acid{4-[3-(2-fluoro-5-trifluoromethyl-benzyl)-thioureido]- phenyl}-amide 671456 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(2-fluoro-5-trifluoromethyl-benzyl)- thioureido]-phenyl}-amide 672416 N-{4-[3-(3,4-Difluoro-benzyl)-thioureido]-phenyl}-2-fluoro-benzamide673 452N-(4-{3-[2-(4-Dimethylamino-3-methyl-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide 674 496 [1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(3-dimethylamino-5-trifluoro-methyl-phenyl)-ethyl]-thioureido}-phenyl)-amide 675 388Furan-2-carboxylic acid {4-[3-(3,4-difluoro-benzyl)-thioureido]-phenyl}-amide 676 406 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3,4-difluoro-benzyl)-thioureido]- phenyl}-amide 677 433N-{4-[3-(3-Chloro-4-fluoro-benzyl)-thioureido]-phenyl}-2-fluoro-benzamide678 495 [1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(3-bromo-phenylsulfanyl)-ethyl]- thioureido}-phenyl)-amide 679477 Furan-2-carboxylic acid(4-{3-[2-(3-bromo-phenylsulfanyl)-ethyl]-thioureido}- phenyl)-amide 680505N-(4-{3-[2-(3-Bromo-phenylsulfanyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide 681 493 [1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(3-bromo-4-methoxy-phenyl)- ethyl]-thioureido}-phenyl)-amide682 493 [1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(5-bromo-2-methoxy-phenyl)- ethyl]-thioureido}-phenyl)-amide683 419 [1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(2-chloro-phenyl)-ethyl]- thioureido}-phenyl)-amide 684 402[1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(2-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-amide 685 419 [1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(4-chloro-phenyl)-ethyl]- thioureido}-phenyl)-amide 686 475[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3,3-diphenyl-propyl)-thioureido]- phenyl}-amide 687 5472-Fluoro-N-(4-{3-[4-(4-methyl-piperazin-1-yl)-3-trifluoromethyl-benzyl]-thioureido}-phenyl)-benzamide 688 469 [1,2,3]Thiadiazole-4-carboxylicacid (4-{3-[2-(3,5-dichloro-phenoxy)-ethyl]- thioureido}-phenyl)-amide689 423 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-chloro-4-fluoro-benzyl)- thioureido]-phenyl}-amide 690 427[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(4-tert-butyl-benzyl)-thioureido]- phenyl}-amide 691 399[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3,5-dimethyl-benzyl)-thioureido]- phenyl}-amide 692 442[1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(4-dimethylamino-3-methyl-phenyl)-ethyl]-thioureido}-phenyl)-amide 693 479[1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(4-bromo-phenoxy)-ethyl]-thioureido}-phenyl)-amide 694 526 [1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(4-iodo-phenoxy)-ethyl]- thioureido}-phenyl)-amide 695 489N-(4-{3-[2-(4-Bromo-phenoxy)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide 696 5362-Fluoro-N-(4-{3-[2-(4-iodo-phenoxy)-ethyl]-thioureido}-phenyl)-benzamide697 461 Furan-2-carboxylic acid(4-{3-[2-(4-bromo-phenoxy)-ethyl]-thioureido}- phenyl)-amide 698 508Furan-2-carboxylic acid (4-{3-[2-(4-iodo-phenoxy)-ethyl]-thioureido}-phenyl)-amide 699 408 Oxazole-4-carboxylic acid{4-[3-(3,4-dichloro-phenyl)-thioureido]- phenyl}-amide 700 424Thiazole-4-carboxylic acid{4-[3-(3,5-dichloro-phenyl)-thioureido]-phenyl}- amide 701 491Thiazole-4-carboxylic acid{4-[3-(3,5-bis-trifluoromethyl-phenyl)-thioureido]- phenyl}-amide 702408 Oxazole-4-carboxylic acid{4-[3-(3,5-dichloro-phenyl)-thioureido]-phenyl}- amide 703 469[1,2,3]Thiadzole-4-carboxylic acid(4-{3-[2-(3,4-dichloro-phenoxy)-ethyl]- thioureido}-phenyl)-amide 704424 Thiazole-4-carboxylic acid{4-[3-(3,4-dichloro-phenyl)-thioureido]-phenyl}- amide 705 458Thiazole-4-carboxylic acid {4-[3-(4-chloro-3-trifluoromethyl-phenyl)-thioureido]-phenyl}-amide 706 400 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(2-phenylamino-ethyl)-thioureido]- phenyl}-amide 707 453[1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(2,4-dichloro-phenyl)-ethyl]- thioureido}-phenyl)-amide 708 452[1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(3-trifluoromethyl-phenyl)-ethyl]- thioureido}-phenyl)-amide709 453 [1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(2,6-dichloro-phenyl)-ethyl]- thioureido}-phenyl)-amide 710 485[1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(3,4-dichloro-phenylsulfanyl)- ethyl]-thioureido}-phenyl)-amide711 503 [1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(2-fluoro-5-trifluoromethyl-phenylsulfanyl)-ethyl]-thioureido}-phenyl)-amide 712 668N-(4-{3-[3-Chloro-5-(3-{4-[([1,2,3]thiadiazole-4-carbonyl)-amino]-phenyl}-thioureido)-phenyl]-thioureido}-phenyl)-[1,2,3]thiadiazole-4-carboxamide713 413 [1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(4-ethyl-phenyl)-ethyl]- thioureido}-phenyl)-amide 714 442Oxazole-4-carboxylic acid {4-[3-(4-chloro-3-trifluoromethyl-phenyl)-thioureido]-phenyl}-amide 715 475 Oxazole-4-carboxylic acid{4-[3-(3,5-bis-trifluoromethyl-phenyl)-thioureido]- phenyl}-amide 716420 [1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(3,4-difluoro-phenyl)-ethyl]- thioureido}-phenyl)-amide 717 452[1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(4-trifluoromethyl-phenyl)-ethyl]- thioureido}-phenyl)-amide718 435 Furan-2-carboxylic acid(4-{3-[2-(3,4-dichloro-phenyl)-ethyl]-thioureido}- phenyl)-amide 719 463N-(4-{3-[2-(3,4-Dichloro-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide 720 420 [1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(3,5-difluoro-phenyl)-ethyl]- thioureido}-phenyl)-amide 721 4122-Fluoro-N-(4-{3-[2-(2-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-benzamide722 429 [1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(4-nitro-phenyl)-ethyl]- thioureido}-phenyl)-amide 723 399[1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(1-methyl-2-phenyl-ethyl)-thioureido]-phenyl}-amide 724 437N-{4-[3-(4-tert-Butyl-benzyl)-thioureido]-phenyl}-2-fluoro-benzamide 725409 N-{4-[3-(3,5-Dimethyl-benzyl)-thioureido]-phenyl}-2-fluoro-benzamide726 400 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(2-hydroxy-1-phenyl-ethyl)- thioureido]-phenyl}-amide 727 4092-Fluoro-N-{4-[3-(1-methyl-1-phenyl-ethyl)-thioureido]-phenyl}-benzamide 728 399 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(1-methyl-1-phenyl-ethyl)- thioureido]-phenyl}-amide 729 405[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(2-chloro-benzyl)-thioureido]- phenyl}-amide 730 388[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(2-fluoro-benzyl)-thioureido]- phenyl}-amide 731 438[1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-trifluoromethyl-benzyl)-thioureido]-phenyl}-amide 732 388 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-fluoro-benzyl)-thioureido]- phenyl}-amide 733 435[1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(2-chloro-phenoxy)-ethyl]-thioureido}-phenyl)-amide 734 479 [1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(3-bromo-phenoxy)-ethyl]- thioureido}-phenyl)-amide 735 418[1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(2-fluoro-phenoxy)-ethyl]-thioureido}-phenyl)-amide 736 418 [1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(3-fluoro-phenoxy)-ethyl]- thioureido}-phenyl)-amide 737 486[1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(2-fluoro-5-trifluoromethyl-phenoxy)-ethyl]-thioureido}-phenyl)-amide 738 384 Furan-2-carboxylicacid (4-{3-[2-(2-fluoro-phenyl)-ethyl]-thioureido}- phenyl)-amide 739435 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(4-bromo-phenyl)-thioureido]- phenyl}-amide 740 374[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(4-fluoro-phenyl)-thioureido]- phenyl}-amide 741 388[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(4-fluoro-benzyl)-thioureido]- phenyl}-amide 742 405[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(4-chloro-benzyl)-thioureido]- phenyl}-amide 743 449[1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-bromo-benzyl)-thioureido]-phenyl}-amide 744 332N-(4-{3-[1-(4-Fluoro-phenyl)-ethyl]-thioureido}-phenyl)-acetamide 745438 Thiazole-4-carboxylic acid{4-[3-(3,4-dichloro-benzyl)-thioureido]-phenyl}- amide 746 455Thiazole-4-carboxylic acid {4-[3-(2-fluoro-5-trifluoromethyl-benzyl)-thioureido]-phenyl}-amide 747 426 Thiazole-4-carboxylic acid{4-[3-(4-tert-butyl-benzyl)-thioureido]-phenyl}- amide 748 374[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(2-fluoro-phenyl)-thioureido]- phenyl}-amide 749 374[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-fluoro-phenyl)-thioureido]- phenyl}-amide 750 526[1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3-iodo-phenoxy)-ethyl]-thioureido}-phenyl)-amide 751 409N-(4-{3-[1-(4-Fluoro-phenyl)-ethyl]-thioureido}-phenyl)-2-phenyl-acetamide 752 425N-(4-{3-[1-(4-Fluoro-phenyl)-ethyl]-thioureido}-phenyl)-2-methoxy-benzamide 753 425N-(4-{3-[1-(4-Fluoro-phenyl)-ethyl]-thioureido}-phenyl)-3-methoxy-benzamide 754 425N-(4-{3-[1-(4-Fluoro-phenyl)-ethyl]-thioureido}-phenyl)-4-methoxy-benzamide 755 4292-Chloro-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-benzamide756 4294-Chloro-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-benzamide757 453 Acetic acid4-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenylcarbamoyl)- phenylester 758 394N-(4-{3-[1-(4-Fluoro-phenyl)-ethyl]-thioureido}-phenyl)-benzamide 759395N-(4-{3-[1-(4-Fluoro-phenyl)-ethyl]-thioureido}-phenyl)-isonicotinamide760 410N-(4-{3-[1-(4-Fluoro-phenyl)-ethyl]-thioureido}-phenyl)-4-hydroxy-benzamide761 4293-Chloro-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-benzamide762 470 [1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(3-fluoro-5-trifluoromethyl-phenyl)-ethyl]-thioureido}-phenyl)-amide 763 520[1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(2,4-bis-trifluoromethyl-phenyl)-ethyl]-thioureido}-phenyl)-amide 764 470 [1,2,3]Thiadiazole-4-carboxylicacid (4-{3-[2-(4-fluoro-3-trifluoromethyl-phenyl)-ethyl]-thioureido}-phenyl)-amide 765 4384-Dimethylamino-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-benzamide 766 470 [1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(2-fluoro-3-trifluoromethyl-phenyl)-ethyl]-thioureido}-phenyl)-amide 767 470[1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(2-fluoro-5-trifluoromethyl-phenyl)-ethyl]-thioureido}-phenyl)-amide 768 510[1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3-iodo-phenyl)-ethyl]-thioureido}-phenyl)-amide 769 470 [1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(4-fluoro-2-trifluoromethyl-phenyl)-ethyl]-thioureido}-phenyl)-amide 770 463[1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3-bromo-phenyl)-ethyl]-thioureido}-phenyl)-amide 771 4272-Fluoro-N-(4-{3-[1-(4-fluoro-phenyl)-propyl]-thioureido}-phenyl)-benzamide 772 4752-Fluoro-N-(4-{3-[(4-fluoro-phenyl)-phenyl-methyl]-thioureido}-phenyl)-benzamide 773 4552-Fluoro-N-(4-{3-[1-(4-fluoro-phenyl)-pentyl]-thioureido}-phenyl)-benzamide 774 4892-Fluoro-N-(4-{3-[1-(4-fluoro-phenyl)-2-phenyl-ethyl]-thioureido}-phenyl)-benzamide 775 4092-Fluoro-N-{4-[3-(1-o-tolyl-ethyl)-thioureido]-phenyl}-benzamide 776 4092-Fluoro-N-{4-[3-(1-m-tolyl-ethyl)-thioureido]-phenyl}-benzamide 777 4252-Fluoro-N-(4-{3-[1-(4-methoxy-phenyl)-ethyl]-thioureido}-phenyl)-benzamide 778 4122-Fluoro-N-(4-{3-[1-(2-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-benzamide 779 429N-(4-{3-[1-(3-Chloro-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide 780 473N-(4-{3-[1-(3-Bromo-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide 781 429N-(4-{3-[1-(4-Chloro-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide 782 4092-Fluoro-N-{4-[3-(1-p-tolyl-ethyl)-thioureido]-phenyl}-benzamide 783 473N-(4-{3-[1-(2-Bromo-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide 784 429N-(4-{3-[1-(2-Chloro-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide 785 4622-Fluoro-N-(4-{3-[1-(2-trifluoromethyl-phenyl)-ethyl]-thioureido}-phenyl)-benzamide 786 4622-Fluoro-N-(4-{3-[1-(3-trifluoromethyl-phenyl)-ethyl]-thioureido}-phenyl)-benzamide 787 4622-Fluoro-N-(4-{3-[1-(4-trifluoromethyl-phenyl)-ethyl]-thioureido}-phenyl)-benzamide 788 4252-Fluoro-N-(4-{3-[1-(2-methoxy-phenyl)-ethyl]-thioureido}-phenyl)-benzamide 789 4252-Fluoro-N-(4-{3-[1-(3-methoxy-phenyl)-ethyl]-thioureido}-phenyl)-benzamide 790 4412-Fluoro-N-(4-{3-[1-(4-fluoro-phenyl)-2-methyl-propyl]-thioureido}-phenyl)-benzamide 791 419N-(4-{3-[1-(3-Cyano-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide792 419N-(4-{3-[1-(4-Cyano-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide793 438N-(4-{3-[1-(4-Dimethylamino-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide 794 438N-(4-{3-[1-(3-Dimethylamino-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide 795 4732-Bromo-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-benzamide796 446 Quinoline-2-carboxylic acid(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}- phenyl)-amide 797 4102-Fluoro-N-{4-[3-(2-hydroxy-1-phenyl-ethyl)-thioureido]-phenyl}-benzamide798 332 2-Fluoro-N-[4-(3-isopropyl-thioureido)-phenyl]-benzamide 799 4452-Fluoro-N-{4-[3-(1-naphthalen-2-yl-ethyl)-thioureido]-phenyl}-benzamide800 4123-Fluoro-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-benzamide801 4124-Fluoro-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-benzamide802 3842-Fluoro-N-{4-[3-(1-furan-2-yl-ethyl)-thioureido]-phenyl}-benzamide 8033952-Fluoro-N-{4-[3-(1-pyridin-4-yl-ethyl)-thioureido]-phenyl}-benzamide804 3972-Fluoro-N-(4-{3-[1-(1-methyl-1H-pyrrol-2-yl)-ethyl]-thioureido}-phenyl)-benzamide 805 4012-Fluoro-N-{4-[3-(1-thiophen-3-yl-ethyl)-thioureido]-phenyl}-benzamide806 445N-{4-[3-(3-Chloro-4-ethoxy-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide807 459N-{4-[3-(3-Chloro-4-propoxy-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide808 459N-{4-[3-(3-Chloro-4-isopropoxy-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide 809 473N-{4-[3-(4-Butoxy-3-chloro-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide810 5222-Fluoro-N-{4-[3-(3-iodo-4-methoxy-phenyl)-thioureido]-phenyl}-benzamide811 475 N-{4-[3-(3-Bromo-4-methoxy-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide 812 520N-(4-{3-[1-(4-Fluoro-phenyl)-ethyl]-thioureido}-phenyl)-2-iodo-benzamide813 346N-(4-{3-[1-(4-Fluoro-phenyl)-ethyl]-thioureido}-phenyl)-propionamide 814286 N-[4-(3-Phenyl-thioureido)-phenyl]-acetamide 815 507N-{5-[({[3,5-bis(trifluoromethyl)benzyl]amino}carbothioyl)amino]-2-pyridinyl}-1,2,3-thiadiazole-4-carboxamide 816 521N-(5-{[({(1S)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}amino)carbothioyl]amino}-2-pyridinyl)-1,2,3-thiadiazole-4-carboxamide 817 520N-(5-{[({(1S)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}amino)carbothioyl]amino}-2-pyridinyl)-1,3-thiazole-4-carboxamide 818 470N-(5-{[({1-[2-fluoro-5-(trifluoromethyl)phenyl]ethyl}amino)carbothioyl]amino}-2-pyridinyl)-1,3-thiazole-4-carboxamide 819 470N-(5-{[({1-[2-fluoro-4-(trifluoromethyl)phenyl]ethyl}amino)carbothioyl]amino}-2-pyridinyl)-1,3-thiazole-4-carboxamide 820 470N-(5-{[({1-[3-fluoro-5-(trifluoromethyl)phenyl]ethyl}amino)carbothioyl]amino}-2-pyridinyl)-1,3-thiazole-4-carboxamide 821 504N-(5-{[({(1S)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}amino)carbonyl]amino}-2-pyridinyl)-1,3-thiazole-4-carboxamide 822 463N-{5-[({[1-(3-bromophenyl)ethyl]amino}carbothioyl)amino]-2-pyridinyl}-1,3-thiazole-4-carboxamide 823 463N-{5-[({[1-(2-bromophenyl)ethyl]amino}carbothioyl)amino]-2-pyridinyl}-1,3-thiazole-4-carboxamide 824 452N-(5-{[({1-[3-(trifluoromethyl)phenyl]ethyl}amino)carbothioyl]amino}-2-pyridinyl)-1,3-thiazole-4-carboxamide 825 486N-(5-{[({1-[4-chloro-3-(trifluoromethyl)phenyl]ethyl}amino)carbothioyl]amino}-2-pyridinyl)-1,3-thiazole-4-carboxamide 826 436N-{5-[({[1-(4-chloro-3-fluorophenyl)ethyl]amino}carbothioyl)amino]-2-pyridinyl}-1,3-thiazole-4-carboxamide 827 436N-{5-[({[1-(4-chloro-2-fluorophenyl)ethyl]amino}carbothioyl)amino]-2-pyridinyl}-1,3-thiazole-4-carboxamide 828 434N-{6-[({[1-(4-fluorophenyl)ethyl]amino}carbothioyl)amino]-3-pyridinyl}-1,2,3,-thiadiazole-4-carboxamide 829 426N-(6-{[({(1S)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}amino)carbothioyl]amino}-3-pyridinyl)-1,2,3-thiadiazole-4-carboxamide

EXAMPLE 830 (METHOD 32) [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(2,5-dichloro-phenyl)-thioureido]-phenyl}-amide

[1077] To a solution of 2,5-dichloroaniline (0.16 g) in tetrahydrofuran(20 mL) is added freshly prepared 1,1′-thiocarbonyldiimidazole (0.20 g)and the mixture is stirred for approximately 30 minutes at roomtemperature. [1,2,3]-Thiadiazole-4-carboxylic acid (4-amino-phenyl)amide (0.22 g) is added to the reaction flask and the mixture is stirredfor approximately 6 hours. The solvent is then removed by evaporationunder reduced pressure and warm acetonitrile (3 mL) is added. After 15hours the mixture is filtered and the collected precipitate is washedwith acetonitrile then diethyl ether, and air dried to provide thedesired product as a white powder.

[1078] Using the above procedure and appropriate starting materials thefollowing compounds were prepared: EX. NO. M + H COMPOUND NAME 831 321N-{4-[3-(3-Chloro-phenyl)-thioureido]-phenyl}-acetamide 832 413N-{4-[3-(3-Chloro-4-methoxy-phenyl)-thioureido]-phenyl}-benzamide 833443N-{4-[3-(3-Chloro-4-methoxy-phenyl)-thioureido]-phenyl}-2-methoxy-benzamide834 443N-{4-[3-(3-Chloro-4-methoxy-phenyl)-thioureido]-phenyl}-3-methoxy-benzamide835 443N-{4-[3-(3-Chloro-4-methoxy-phenyl)-thioureido]-phenyl}-4-methoxy-benzamide836 431N-{4-[3-(3-Chloro-4-methoxy-phenyl)-thioureido]-phenyl}-4-methoxy-benzamide837 431N-{4-[3-(3-Chloro-4-methoxy-phenyl)-thioureido]-phenyl}-3-fluoro-benzamide838 431N-{4-[3-(3-Chloro-4-methoxy-phenyl)-thioureido]-phenyl}-4-fluoro-benzamide839 437 Furan-2-carboxylic acid{4-[3-(3,5-dichloro-4-methoxy-phenyl)-thioureido]- phenyl}-amide 840 511{4-[3-(5-Bromo-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-carbamic acidhexyl ester 841 481 Hexanoic acid{4-[3-(5-bromo-2,4-dimethoxy-phenyl)-thioureido]-phenyl}- amide 842 505N-{4-[3-(5-Bromo-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide 843 477 Furan-2-carboxylic acid{4-[3-(5-bromo-2,4-dimethoxy-phenyl)-thioureido]- phenyl}-amide 844 501N-{4-[3-(5-Bromo-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2-methyl-benzamide 845 517N-{4-[3-(5-Bromo-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-4-methoxy-benzamide 846 395N-{4-[3-(5-Chloro-2-ethoxy-4-methoxy-phenyl)-thioureido]-phenyl}-acetamide847 395N-{4-[3-(5-Chloro-4-ethoxy-2-methoxy-phenyl)-thioureido]-phenyl}-acetamide848 423N-{4-[3-(2-Butoxy-5-chloro-4-methoxy-phenyl)-thioureido]-phenyl}-acetamide849 423N-{4-[3-(4-Butoxy-5-chloro-2-methoxy-phenyl)-thioureido]-phenyl}-acetamide850 457N-{4-[3-(2-Benzyloxy-5-chloro-4-methoxy-phenyl)-thioureido]-phenyl}-acetamide 851 457N-{4-[3-(4-Benzyloxy-5-chloro-2-methoxy-phenyl)-thioureido]-phenyl}-acetamide 852 421 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-chloro-4-methoxy-phenyl)-thioureido]- phenyl}-amide 853 4242-{4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro-5-methoxy-phenoxy}-acetamide 854 367N-{4-[3-(5-Chloro-2-hydroxy-4-methoxy-phenyl)-thioureido]-phenyl}-acetamide855 367N-{4-[3-(3-Chloro-4-methylsulfanyl-phenyl)-thioureido]-phenyl}-acetamide856 447N-[4-(3-{3-Chloro-4-[methyl-(1-methyl-piperidin-4-yl)-amino]-phenyl}-thioureido)-phenyl]-acetamide 857 426N-(4-{3-[3-Chloro-4-(methyl-phenyl-amino)-phenyl]-thioureido}-phenyl)-acetamide 858 509N-[4-(3-{4-[(1-Benzyl-pyrrolidin-3-yl)-methyl-amino]-3-chloro-phenyl}-thioureido)-phenyl]-acetamide 859 418N-(4-{3-[3-Chloro-4-(cyclopentyl-methyl-amino)-phenyl]-thioureido}-phenyl)-acetamide 860 433N-[4-(3-{3-Chloro-4-[methyl-(1-methyl-pyrrolidin-3-yl)-amino]-phenyl}-thioureido)-phenyl]-acetamide 861 419 Furan-2-carboxylic acid{4-[3-(3-chloro-4-methylsulfanyl-phenyl)-thioureido]- phenyl}-amide 862447N-{4-[3-(3-Chloro-4-methylsulfanyl-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide 863 465N-{4-[3-(3-Chloro-4-methylsulfanyl-phenyl)-thioureido]-phenyl}-2,6-difluoro-benzamide 864 445N-{4-[3-(5-Chloro-2-methoxy-4-methyl-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide 865 441N-{4-[3-(5-Chloro-2-methoxy-4-methyl-phenyl)-thioureido]-phenyl}-2-methyl-benzamide 866 434 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-chloro-4-dimethylamino-phenyl)- thioureido]-phenyl}-amide 867444N-{4-[3-(3-Chloro-4-dimethylamino-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide 868 517 [1,2,3]Thiadiazole-4-carboxylic acid[4-(3-{3-chloro-4-[methyl-(1-methyl-piperidin-4-yl)-amino]-phenyl}-thioureido)-phenyl]-amide 869 579[1,2,3]Thiadiazole-4-carboxylic acid[4-(3-{4-[(1-benzyl-pyrrolidin-3-yl)-methyl-amino]-3-chloro-phenyl}-thioureido)-phenyl]-amide 870 527N-[4-(3-{3-Chloro-4-[methyl-(1-methyl-piperidin-4-yl)-amino]-phenyl}-thioureido)-phenyl]-2-fluoro-benzamide 871 435[1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(5-chloro-2-methoxy-4-methyl-phenyl)-thioureido]-phenyl}-amide 872 589N-[4-(3-{4-[(1-Benzyl-pyrrolidin-3-yl)-methyl-amino]-3-chloro-phenyl}-thioureido)-phenyl]-2-fluoro-benzamide 873 501 Furan-2-carboxylic acid{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-3-trifluoromethyl-phenyl}-amide 874 3662-Fluoro-N-[4-(3-phenyl-thioureido)-phenyl]-benzamide 875 338Furan-2-carboxylic acid [4-(3-phenyl-thioureido)-phenyl]-amide 876 356[1,2,3]Thiadiazole-4-carboxylic acid[4-(3-phenyl-thioureido)-phenyl]-amide 877 365N-(4-{3-[3-Chloro-4-(1-hydroxy-ethyl)-phenyl]-thioureido}-phenyl)-acetamide878 435 [1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[3-chloro-4-(1-hydroxy-ethyl)-phenyl]- thioureido}-phenyl)-amide879 365N-(4-{3-[3-Chloro-4-(2-hydroxy-ethyl)-phenyl]-thioureido}-phenyl)-acetamide880 445N-(4-{3-[3-Chloro-4-(1-hydroxy-ethyl)-phenyl]-thioureido}-phenyl)-2-fluoro-benzamide 881 417 Furan-2-carboxylic acid(4-{3-[3-chloro-4-(1-hydroxy-ethyl)-phenyl]-thioureido}- phenyl)-amide882 371 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-amino-phenyl)-thioureido]-phenyl}- amide 883 501Furan-2-carboxylic acid{4-[3-(3-bromo-4-trifluoromethoxy-phenyl)-thioureido]- phenyl}-amide 884423 N-{4-[3-(3-tert-Butyl-phenyl)-thioureido)-phenyl}-2-fluoro-benzamide885 440 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(4-chloro-3,5-dichloro-phenyl)- thioureido]-phenyl}-amide 986 485N-{4-[3-(1-Benzofuran-2-yl-ethyl)-thioureido]-phenyl}-2-trifluoromethyl-benzamide987 412N-(4-Fluoro-phenyl)-4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-benzamide988 446 Isoquinoline-1-carboxylic acid(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)- amide 989 468Isoquinoline-1-carboxylic acid(4-[3-(1-benzofuran-2-yl-ethyl)-thioureido]-phenyl}- amide 993 506Isoquinoline-1-carboxylic acid(4-{3-[1-(4-bromo-phenyl)-ethyl]-thioureido}-phenyl)- amide 994 453Isoquinoline-1-carboxylic acid(4-{3-[1-(4-cyano-phenyl)-ethyl]-thioureido}-phenyl)- amide 995 435Benzofuran-2-carboxylic acid(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)- amide 996 457Benzofuran-2-carboxylic acid{4-[3-(1-benzofuran-2-yl-ethyl)-thioureido]-phenyl}- amide 997 495Benzofuran-2-carboxylic acid(4-{3-[1-(4-bromo-phenyl)-ethyl]-thioureido}-phenyl)- amide 998 442Benzofuran-2-carboxylic acid(4-{3-[1-(4-cyano-phenyl)-ethyl]-thioureido}-phenyl)- amide 999 446Isoquinoline-3-carboxylic acid(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)- amide 1000 468Isoquinoline-3-carboxylic acid{4-[3-(1-benzofuran-2-yl-ethyl)-thioureido]-phenyl}- amide 1001 453Isoquinoline-3-carboxylic acid(4-{3-[1-(4-cyano-phenyl)-ethyl]-thioureido}-phenyl)- amide 1002 506Isoquinoline-3-carboxylic acid(4-{3-[1-(4-bromo-phenyl)-ethyl]-thioureido}-phenyl)- amide 1003 446Quinoline-3-carboxylic acid(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)- amide 1004 446Quinoline-4-carboxylic acid(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)- amide 1005 446Quinoline-6-carboxylic acid(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)- amide 1006 446Quinoline-8-carboxylic acid(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)- amide 1007 462N-(4-{3-[1-(4-Fluoro-phenyl)-ethyl]-thioureido}-phenyl)-2-trifluoromethyl-benzamide1008 4192-Cyano-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-benzamide1009 473N-{4-[3-(3-Chloro-4-isobutoxy-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide1010 4142-Fluoro-N-{4-[3-(3-fluoro-4-methoxy-phenyl)-thioureido]-phenyl}-benzamide1011 475N-(4-{3-[3-Chloro-4-(2-methoxy-ethoxy)-phenyl]-thioureido}-phenyl)-2-fluoro-benzamide 1012 3982-Fluoro-N-{4-[3-(3-fluoro-4-methyl-phenyl)-thioureido]-phenyl}-benzamide1013 4642-Fluoro-N-{4-[3-(4-methoxy-3-trifluoromethyl-phenyl)-thioureido]-phenyl}-benzamide1014 449N-{4-[3-(2-Amino-5-trifluoromethyl-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide1015 459N-(4-{3-[1-(3-Chloro-4-methoxy-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide 1016 417N-{4-[3-(5-Chloro-2-hydroxy-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide1017 435N-{4-[3-(1-Benzofuran-2-yl-ethyl)-thioureido]-phenyl}-2-fluoro-benzamide1018 4482-Fluoro-N-{4-[3-(4-methyl-3-trifluoromethylphenyl)-thioureido]-phenyl}-benzamide1019 473(S)-N-(4-{3-[1-(4-Bromo-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide1020 473N-(4-{3-[(1R)-1-(4-Bromo-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide1021 4942-Fluoro-N-(4-{3-[2-methoxy-4-(2,2,2-trifluoro-ethoxy)-phenyl]-thioureido}-phenyl)-benzamide 1022 399N-{4-[3-(2-Amino-5-fluorophenyl)-thioureido]-phenyl}-2-fluoro-benzamide1023 502N-(4-{3-[1-(4-Dimethylsulfamoyl-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide 1024 5422-Fluoro-N-[4-(3-{1-[4-(piperidine-1-sulfonyl)-phenyl]-ethyl}-thioureido)-phenyl]-benzamide 1025 562N-(4-{3-[2,4-Bis-(2,2,2-trifluoro-ethoxy)-phenyl]-thioureido}-phenyl)-2-fluoro-benzamide 1026 4092-Fluoro-N-{4-[3-((1S)-1-p-tolyl-ethyl)-thioureido]-phenyl}-benzamide1027 4092-Fluoro-N-{4-[3-((1R)-1-p-tolyl-ethyl)-thioureido]-phenyl}-benzamide1028 3942-Fluoro-N-{4-[3-((1S)-1-phenyl-ethyl)-thioureido]-phenyl}-benzamide1029 429N-(4-{3-[(1R)-1-(4-Chloro-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide1030 429N-(4-{3-[(1S)-1-(4-Chloro-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide1031 3942-Fluoro-N-{4-[3-((1R)-1-phenyl-ethyl)-thioureido]-phenyl}-benzamide1032 432N-(4-{3-[1-(4-Cyano-phenyl)-ethyl]-thioureido}-phenyl)-2-methoxy-benzamide1033 447N-{4-[3-(1-Benzofuran-2-yl-ethyl)-thioureido]-phenyl}-2-methoxy-benzamide1034 485N-(4-{3-[1-(4-Bromo-phenyl)-ethyl]-thioureido}-phenyl)-2-methoxy-benzamide1035 4193-Cyano-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-benzamide1036 462N-(4-{3-[1-(4-Fluoro-phenyl)-ethyl]-thioureido}-phenyl)-4-trifluoromethyl-benzamide1037 4194-Cyano-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-benzamide1038 4692-Fluoro-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-2,3,5,6-tetramethyl-phenyl)-benzamide 1039 480N-(4-{3-[1-(4-Cyano-phenyl)-ethyl]-thioureido}-2,5-dimethoxy-phenyl)-2-fluoro-benzamide 1040 4732-Fluoro-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-2,5-dimethoxy-phenyl)-benzamide 1041 530N-{3,5-Dichloro-4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide 1042 447N-(3-Chloro-4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide1043 4802,3,4,5-Tetrafluoro-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-3-methyl-phenyl)-benzamide 1044 4622,4,5-Trifluoro-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-3-methyl-phenyl)-benzamide 1045 4272-Fluoro-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-3-methyl-phenyl)-benzamide1046 4572-Fluoro-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-2-methoxy-5-methyl-phenyl)-benzamide 1047 4432-Fluoro-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-3-methoxy-phenyl)-benzamide1048 570N-(2,6-Dibromo-4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide 1049 4802-Fluoro-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-2-trifluoromethyl-phenyl)-benzamide 1050 541N-(4-{3-[1-(4-Bromo-phenyl)-ethyl]-thioureido}-2-trifluoromethyl-phenyl)-2-fluoro-benzamide 1051 487N-(4-{3-[1-(4-Cyano-phenyl)-ethyl]-thioureido}-2-trifluoromethyl-phenyl)-2-fluoro-benzamide 1052 503N-{4-[3-(1-Benzofuran-2-yl-ethyl)-thioureido]-2-trifluoromethyl-phenyl}-2-fluoro-benzamide 1053 447N-(2-Chloro-4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide1054 454N-(2-Chloro-4-{3-[1-(4-cyano-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide1055 437N-(2-Cyano-4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide1056 498N-(4-{3-[1-(4-Bromo-phenyl)-ethyl]-thioureido}-2-cyano-phenyl)-2-fluoro-benzamide1057 445N-(2-Cyano-4-{3-[1-(4-cyano-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide1058 460N-{4-[3-(1-Benzofuran-2-yl-ethyl)-thioureido]-2-cyano-phenyl}-2-fluoro-benzamide1059 517N-(2-Benzoyl-4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide1060 4272-Fluoro-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-2-methyl-phenyl)-benzamide1061 487N-(4-{3-[1-(4-Bromo-phenyl)-ethyl]-thioureido}-2-methyl-phenyl)-2-fluoro-benzamide1062 434N-(4-{3-[1-(4-Cyano-phenyl)-ethyl]-thioureido}-2-methyl-phenyl)-2-fluoro-benzamide1063 449N-{4-[3-(1-Benzofuran-2-yl-ethyl)-thioureido]-2-methyl-phenyl}-2-fluoro-benzamide1064 456N-(2-Dimethylamino-4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide 1065 526N-(2-Benzyloxy-4-{3-[1-(4-cyano-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide 1066 519N-(2-Benzyloxy-4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide 1067 603N-[4-{3-[1-(4-Bromo-phenyl)-ethyl]-thioureido}-2-(2-morpholin-4-yl-ethoxy)-phenyl]-2-fluoro-benzamide 1068 603N-[4-{3-[1-(4-Bromo-phenyl)-ethyl]-thioureido}-2-(2-morpholin-4-yl-ethoxy)-phenyl]-2-fluoro-benzamide 1069 5422-Fluoro-N-[4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-2-(2-morpholin-4-yl-ethoxy)-phenyl]-benzamide 1070 485N-(2-Butoxy-4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide1071 492N-(2-Butoxy-4-{3-[1-(4-cyano-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide1072 589N-[4-{3-[1-(4-Bromo-phenyl)-ethyl]-thioureido}-2-(2-diethylamino-ethoxy)-phenyl]-2-fluoro-benzamide 1073 528N-(2-(2-Diethylamino-ethoxy)-4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide 1074 589N-[4-{3-[1-(4-Bromo-phenyl)-ethyl]-thioureido}-2-(2-diethylamino-ethoxy)-phenyl]-2-fluoro-benzamide 1075 457N-(2-Ethoxy-4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide1076 464N-(4-{3-[1-(4-Cyano-phenyl)-ethyl]-thioureido}-2-ethoxy-phenyl)-2-fluoro-benzamide1077 4682-Fluoro-N-[4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-2-(2-nitrilo-ethoxy)-phenyl]-benzamide 1078 475N-[4-{3-[1-(4-Cyano-phenyl)-ethyl]-thioureido}-2-(2-nitrilo-ethoxy)-phenyl]-2-fluoro-benzamide 1079 4432-Fluoro-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-2-methoxy-phenyl)-benzamide1080 4892-Fluoro-N-(5-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-biphenyl-2-yl)-benzamide1081 514 Isoquinoline-1-carboxylic acid(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-2-trifluoromethyl-phenyl)-amide 1082 503 Benzofuran-2-carboxylic acid(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-2-trifluoromethyl-phenyl)-amide 1083 514 Isoquinoline-3-carboxylic acid(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-2-trifluoromethyl-phenyl)-amide 1084 471 Isoquinoline-1-carboxylic acid(2-cyano-4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}- phenyl)-amide1085 460 Benzofuran-2-carboxylic acid(2-cyano-4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}- phenyl)-amide1086 471 Isoquinoline-3-carboxylic acid(2-cyano-4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}- phenyl)-amide1087 460 Isoquinoline-1-carboxylic acid(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-2-methyl- phenyl)-amide1088 449 Benzofuran-2-carboxylic acid(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-2-methyl- phenyl)-amide1089 460 Isoquinoline-3-carboxylic acid(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-2-methyl- phenyl)-amide1090 396 Pyrazine-2-carboxylic acid(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-amide 1091 401Thiophene-2-carboxylic acid(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)- amide 1092 401Thiophene-3-carboxylic acid(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)- amide 1093 5002-Isopropyl-thiazole-4-carboxylic acid{4-[3-(4-chloro-3-trifluoromethyl-phenyl)- thioureido]-phenyl}-amide1094 466 2-Isopropyl-thiazole-4-carboxylic acid{4-[3-(3,5-dichloro-phenyl)-thioureido]-phenyl}- amide 1095 4662-Isopropyl-thiazole-4-carboxylic acid{4-[3-(3,4-dichloro-phenyl)-thioureido]-phenyl}- amide 1096 5342-Isopropyl-thiazole-4-carboxylic acid{4-[3-(3,5-bis-trifluoromethyl-phenyl)- thioureido]-phenyl}-amide 1097480 2-Butyl-thiazole-4-carboxylic acid{4-[3-(3,4-dichloro-phenyl)-thioureido]-phenyl}- amide 1098 5142-Butyl-thiazole-4-carboxylic acid{4-[3-(4-chloro-3-trifluoromethyl-phenyl)- thioureido]-phenyl}-amide1099 480 2-Butyl-thiazole-4-carboxylic acid{4-[3-(3,5-dichloro-phenyl)-thioureido]-phenyl}- amide 1100 5482-Butyl-thiazole-4-carboxylic acid{4-[3-(3,5-bis-trifluoromethyl-phenyl)-thioureido]- phenyl}-amide 1101438 2-Methyl-thiazole-4-carboxylic acid{4-[3-(3,5-dichloro-phenyl)-thioureido]-phenyl}- amide 1102 4382-Methyl-thiazole-4-carboxylic acid{4-[3-(3,4-dichloro-phenyl)-thioureido]-phenyl}- amide 1103 5052-Methyl-thiazole-4-carboxylic acid{4-[3-(3,5-bis-trifluoromethyl-phenyl)-thioureido]- phenyl}-amide 1104534 2-Phenyl-thiazole-4-carboxylic acid{4-[3-(4-chloro-3-trifluoromethyl-phenyl)- thioureido]-phenyl}-amide1105 500 2-Phenyl-thiazole-4-carboxylic acid{4-[3-(3,5-dichloro-phenyl)-thioureido]-phenyl}- amide 1106 5002-Phenyl-thiazole-4-carboxylic acid{4-[3-(3,4-dichloro-phenyl)-thioureido]-phenyl}- amide 1107 5682-Phenyl-thiazole-4-carboxylic acid{4-[3-(3,5-bis-trifluoromethyl-phenyl)-thioureido]- phenyl}-amide 11084012-Fluoro-N-{4-[3-(1-thiazol-2-yl-ethyl)-thioureido]-phenyl}-benzamide1109 5882-Fluoro-N-[4-(3-{1-[1-(toluene-4-sulfonyl)-1H-indol-2-yl]-ethyl}-thioureido)-phenyl]-benzamide 1110 4462-Fluoro-N-{4-[3-(1-quinolin-2-yl-ethyl)-thioureido]-phenyl}-benzamide1111 4462-Fluoro-N-{4-[3-(1-quinolin-4-yl-ethyl)-thioureido]-phenyl}-benzamide1112 4462-Fluoro-N-{4-[3-(1-isoquinolin-3-yl-ethyl)-thioureido]-phenyl}-benzamide1113 4462-Fluoro-N-{4-[3-(1-isoquinolin-1-yl-ethyl)-thioureido]-phenyl}-benzamide1114 4462-Fluoro-N-{4-[3-(1-quinolin-6-yl-ethyl)-thioureido]-phenyl}-benzamide1115 4462-Fluoro-N-{4-[3-(1-quinolin-3-yl-ethyl)-thioureido]-phenyl}-benzamide1116 4132-Methoxy-N-{4-[3-(1-thiophen-3-yl-ethyl)-thioureido]-phenyl}-benzamide

EXAMPLE 886 (METHOD 33) [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3,5-dichloro-phenyl)-thioureido]-phenyl}-amide

[1079] To a solution of 3,5-dichloroaniline (0.16 g) in tetrahydrofuran(20 mL) is added freshly prepared 1,1′-thiocarbonyl-di-(1,2,4)-triazole(0.20 g) and the mixture is for approximately 30 minutes at roomtemperature. [1,2,3]-Thiadiazole-4-carboxylic acid (4-amino-phenyl)amide (0.22 g) is added to the reaction flask and the mixture is stirredfor approximately 6 hours. The solvent is then removed by evaporationunder reduced pressure and warm acetonitrile (3 mL) is added. After 15hours the mixture is filtered and the collected precipitate is washedwith acetonitrile then diethyl ether, and air dried to provide thedesired product as a white powder. [M+H] 424.

[1080] Using the above procedure and appropriate starting materials thefollowing compounds were prepared: EX. NO. M + H COMPOUND NAME 887 465N-{4-[3-(3,5-Dichloro-4-methoxy-phenyl)-thioureido]-phenyl}-3-fluoro-benzamide888 477N-{4-[3-(3,5-Dichloro-4-methoxy-phenyl)-thioureido]-phenyl}-2-methoxy-benzamide 889 465N-{4-[3-(3,5-Dichloro-4-methoxy-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide 890 477N-{4-[3-(3,5-Dichloro-4-methoxy-phenyl)-thioureido]-phenyl}-3-methoxy-benzamide 891 399N-{4-[3-(3,5-Dichloro-2-methoxy-4-methyl-phenyl)-thioureido]-phenyl}-acetamide 892 365N-{4-[3-(3-Chloro-4-methoxy-5-methyl-phenyl)-thioureido]-phenyl}-acetamide 893 331 N-{4-[3-(2-Nitro-phenyl)-thioureido]-phenyl}-acetamide894 331 N-{4-[3-(4-Nitro-phenyl)-thioureido]-phenyl}-acetamide 895 477N-{4-[3-(3,5-Dichloro-4-methoxy-phenyl)-thioureido]-phenyl}-4-methoxy-benzamide 896 351 N-{4-[3-(2-Chloro-5-methoxy-phenyl)-thioureido]-phenyl-acetamide 897 4282-{4-[3-(4-Acetylamino-phenyl)-thioureido]-2,6-dichloro-phenoxy}-acetamide898 443{4-[3-(4-Acetylamino-phenyl)-thioureido]-2,6-dichloro-phenoxy}-aceticacid methyl ester 899 457{4-[3-(4-Acetylamino-phenyl)-thioureido]-2,6-dichloro-phenoxy}-aceticacid ethyl ester 900 447N-{4-[3-(3,5-Dichloro-4-phenoxy-phenyl)-thioureido]-phenyl}-acetamide901 410N-(4-{3-[3,5-Dichloro-4-(2-nitrilo-ethoxy)-phenyl]-thioureido}-phenyl)-acetamide 902 485 {4-83-(4-Acetylamino-phenyl)-thioureido]-2,6-dichloro-phenoxy}-acetic acidtert-butyl ester 903 469 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3,5-dichloro-2-methoxy-4-methyl-phenyl)-thioureido]-phenyl}-amide 904 335N-{4-[3-(3-Chloro-4-methyl-phenyl)-thioureido]-phenyl}-acetamide 905 335N-{4-[3-(5-Chloro-2-methyl-phenyl)-thioureido]-phenyl}-acetamide 906 703N-{4-[3-(4-{4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro-phenyldisulfanyl}-3-chloro-phenyl)-thioureido]-phenyl}-acetamide 907 369N-{4-[3-(3,5-Dichloro-4-methyl-phenyl)-thioureido]-phenyl}-acetamide 908598N-{4-[3-(3,5-Diiodo-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-acetamide909 504N-{4-[3-(3,5-Dibromo-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-acetamide910 317 N-{4-[3-(6-Methoxy-pyridin-3-yl)-thioureido]-phenyl}-acetamide911 347N-{4-[3-(2,6-Dimethoxy-pyridin-3-yl)-thioureido]-phenyl}-acetamide 912457 Acetic acid2-{4-[3-(4-acetylamino-phenyl)-thioureido]-2,6-dichloro-phenoxy}- ethylester 913 365 4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro-benzoicacid 914 346N-{4-[3-(3-Chloro-4-cyano-phenyl)-thioureido]-phenyl}-acetamide 915 512N-(4-{3-[5-Chloro-2-(4-chloro-phenoxy)-4-pyrrol-1-yl-phenyl]-thioureido}-phenyl)-acetamide 916 355N-{4-[3-(3,4-Dichloro-phenyl)-thioureido]-phenyl}-acetamide 917 339N-{4-[3-(3-Chloro-4-fluoro-phenyl)-thioureido]-phenyl}-acetamide 918 447N-{4-[3-(3-Chloro-4-iodo-phenyl)-thioureido]-phenyl}-acetamide 919 400N-{4-[3-(4-Bromo-3-chloro-phenyl)-thioureido]-phenyl}-acetamide 920 424N-[4-(3-{4-[Bis-(2-hydroxy-ethyl)-amino]-3-chloro-phenyl}-thioureido)-phenyl]-acetamide 921 434N-(4-{3-[3-Chloro-4-(hexyl-methyl-amino)-phenyl]-thioureido}-phenyl)-acetamide 922 406N-(4-{3-[3-Chloro-4-(isobutyl-methyl-amino)-phenyl]-thioureido}-phenyl)-acetamide 923 389N-{4-[3-(3-Chloro-4-trifluoromethyl-phenyl)-thioureido]-phenyl}-acetamide924 441 Furan-2-carboxylic acid{4-[3-(3-chloro-4-trifluoromethyl-phenyl)-thioureido]- phenyl}-amide 925459 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-chloro-4-trifluoromethyl-phenyl)- thioureido]-phenyl}-amide 926469N-{4-[3-(3-Chloro-4-trifluoromethyl-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide 927 435N-{4-[3-(3,4-Dichloro-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide 928407 Furan-2-carboxylic acid{4-[3-(3,4-dichloro-phenyl)-thioureido]-phenyl}-amide 929 425[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3,4-dichloro-phenyl)-thioureido]- phenyl}-amide 930 480N-{4-[3-(4-Bromo-3-chloro-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide931 527N-{4-[3-(3-Chloro-4-iodo-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide932 452 Furan-2-carboxylic acid{4-[3-(4-bromo-3-chloro-phenyl)-thioureido]-phenyl}- amide 933 499Furan-2-carboxylic acid{4-[3-(3-chloro-4-iodo-phenyl)-thioureido]-phenyl}- amide 934 391Furan-2-carboxylic acid{4-[3-(3-chloro-4-fluoro-phenyl)-thioureido]-phenyl}- amide 935 470[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(4-bromo-3-chloro-phenyl)-thioureido]- phenyl}-amide 936 517[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-chloro-4-iodo-phenyl)-thioureido]- phenyl}-amide 937 419N-{4-[3-(3-Chloro-4-fluoro-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide938 409 [1,2,3]Thiadiazole-4-carboxylicacid{4-[3-(3-chloro-4-fluoro-phenyl)-thioureido]- phenyl}-amide 939 388N-{4-[3-(3-Chloro-4-isoxazol-5-yl-phenyl)-thioureido]-phenyl}-acetamide940 387N-(4-{3-[3-Chloro-4-(1H-pyrazol-3-yl)-phenyl]-thioureido}-phenyl)-acetamide941 355 N-{4-[3-(2,3-Dichloro-phenyl)-thioureido]-phenyl}-acetamide 942435 N-{4-[3-(2,3-Dichloro-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide943 407 Furan-2-carboxylic acid{4-[3-(2,3-dichloro-phenyl)-thioureido]-phenyl}-amide 944 425[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(2,3-dichloro-phenyl)-thioureido]- phenyl}-amide 945 355N-{4-[3-(2,5-Dichloro-phenyl)-thioureido]-phenyl}-acetamide 946 435N-{4-[3-(2,5-Dichloro-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide 947407 Furan-2-carboxylic acid{4-[3-(2,5-dichloro-phenyl)-thioureido]-phenyl}-amide 948 355N-{4-[3-(3,5-Dichloro-phenyl)-thioureido]-phenyl}-acetamide 949 435N-{4-[3-(3,5-Dichloro-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide 950407 Furan-2-carboxylic acid{4-[3-(3,5-dichloro-phenyl)-thioureido]-phenyl}-amide 951 390N-{4-[3-(3,4,5-Trichloro-phenyl)-thioureido]-phenyl}-acetamide 952 4702-fluoro-N-{4-[3-(3,4,5-trichloro-phenyl)-thioureido]-phenyl}-benzamide953 442 Furan-2-carboxylic acid{4-[3-(3,4,5-trichloro-phenyl)-thioureido]-phenyl}- amide 954 460[1,2,3]Thiadiazole-4-carboxylicacid{4-[3-(3,4,5-trichloro-phenyl)-thioureido]- phenyl}-amide 955 458[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-chloro-4-isoxazol-5-yl-phenyl)- thioureido]-phenyl}-amide 956457 [1,2,3]Thiadiazole-4-carboxylicacid(4-{3-[3-chloro-4-(1H-pyrazol-3-yl)-phenyl]-thioureido}-phenyl)-amide 957 391 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-chloro-phenyl)-thioureido]-phenyl}- amide 958 373Furan-2-carboxylic acid{4-[3-(3-chloro-phenyl)-thioureido]-phenyl}-amide 959 401N-{4-[3-(3-Chloro-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide 960 373Furan-2-carboxylic acid{4-[3-(4-chloro-phenyl)-thioureido]-phenyl}-amide 961 401N-{4-[3-(4-Chloro-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide 962 391[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(4-chloro-phenyl)-thioureido]-phenyl}- amide 963 401N-{4-[3-(2-Chloro-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide 964 3963-(3-{4-[(Furan-2-carbonyl)-amino]-phenyl}-thioureido)-benzoic acidmethyl ester 965 4243-{3-[4-(2-Fluoro-benzoylamino)-phenyl]-thioureido}-benzoic acid methylester 966 4143-(3-{4-[([1,2,3]Thiadiazole-4-carbonyl)-amino]-phenyl}-thioureido)-benzoicacid methyl ester 967 409N-[4-[[[[3-(Aminocarbonyl)phenyl]amino]thioxomethyl]amino]phenyl]-2-fluoro-benzamide 968 373 Furan-2-carboxylic acid{4-[3-(2-chloro-phenyl)-thioureido]-phenyl}-amide 969 381Furan-2-carboxylic acid{4-[3-(3-carbamoyl-phenyl)-thioureido]-phenyl}-amide 970 399[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-carbamoyl-phenyl)-thioureido]- phenyl}-amide 971 391[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(2-chloro-phenyl)-thioureido]-phenyl}- amide 972 356Furan-2-carboxylic acid{4-[3-(3-fluoro-phenyl)-thioureido]-phenyl}-amide 973 383Furan-2-carboxylic acid {4-[3-(3-nitro-phenyl)-thioureido]-phenyl}-amide974 411 2-Fluoro-N-{4-[3-(3-nitro-phenyl)-thioureido]-phenyl}-benzamide975 422 Furan-2-carboxylic acid{4-[3-(3-trifluoromethoxy-phenyl)-thioureido]-phenyl}- amide 976 4502-Fluoro-N-{4-[3-(3-trifluoromethoxy-phenyl)-thioureido]-phenyl}-benzamide977 384 2-Fluoro-N-{4-[3-(3-fluoro-phenyl)-thioureido]-phenyl}-benzamide978 410 3-{3-[4-(2-Fluoro-benzoylamino)-phenyl]-thioureido}-benzoic acid979 382 3-(3-{4-[(Furan-2-carbonyl)-amino]-phenyl}-thioureido)-benzoicacid 980 408N-{4-[3-(3-Acetyl-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide 981 502N-{4-[3-(3-Butylsulfamoyl-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide982 380 Furan-2-carboxylic acid {4-[3-(3-acetyl-phenyl)-thioureido]-phenyl}-amide 983 447 Furan-2-carboxylicacid (4-{3-[3-(2-hydroxy-ethanesulfonyl)-phenyl]-thioureido}-phenyl)-amide 984 4752-Fluoro-N-(4-{3-[3-(2-hydroxy-ethanesulfonyl)-phenyl]-thioureido}-phenyl)-benzamide 985 474 Furan-2-carboxylic acid{4-[3-(3-butylsulfamoyl-phenyl)-thioureido]-phenyl}- amide

EXAMPLE 986 (METHOD 57) 1-(4-Fluoro-phenyl)-2-methyl-propan-1-ol

[1081] To solution of 4-fluorobenzaldehyde (2.0 g) in diethyl ether (40mL) at 0° C. is added dropwise isopropylmagesium bromide (2.0 M, 9.6 mL)with stirring. After 1.5 hours the reaction is quenched with aqueousammonium chloride and extracted with diethyl ether. The diethyl etherextracts are washed with saturated sodium chloride, dried over anhydrousmagnesium sulfate, flitered and evaporated to give an oil. The oil ispurifed by silica gel chromatography eluting with 10%dichloromethane-hexanes to give the product, a yellow oil (1.76 g).

EXAMPLE 987 (METHOD 58) 1-(4-Fluoro-phenyl)-2-methyl-propan-1-one

[1082] To a solution of 1-(4-Fluoro-phenyl)-2-methyl-propan-1-ol (1.6 g)in acetone (10 mL) at 0° C. is added Jones reagent (20 mL) withstirring. After 10 minutes excess Jones reagent is destroyed by additionof isopropyl alcohol. Diethyl ether is added followed by anhydrousmagnesium and the mixture is filtered and evaporated to give theproduct, a yellow oil (1.2 g).

EXAMPLE 988 (METHOD 59) 3-Dimethylamino-5-trifluoromethyl-benzonitrile

[1083] To a solution of 3-dimethylamino-5-trifluoromethylbromobenzene(7.3 g) in N,N-dimethylformamide (20 mL) is added cuprous cyanide (2.7g) and the reaction heated at reflux for 12 hours. The reaction isdiluted with water (40 mL) and dichloromethane is added. Thedichloromethane fraction is washed with concentrated ammonium hydroxide,then water. The solution is dried over anhydrous magnesium sulfate,filtered and concentrated to give a yellow solid which is recrystallizedfrom hexanes to give a yellow solid, (4.7 g).

[1084] The foregoing compounds were tested for activity as herpes virusinhibitors using the following assays.

Human Cytomegalovirus

[1085] Yield Assay.

[1086] Monolayer cultures of human foreskin fibroblasts are infectedwith HCMV wild-type, typically at a multiplicity of infection equal to0.2, in the presence of inhibitor compound (varying concentrations). Atthree days post-infection, total virus produced in these cultures (i.e.virus yield) is assessed by harvesting and titering the virus in 12-wellplates of cultured human foreskin fibroblasts (done in the absence ofinhibitor). Plaques are quantified at 2 weeks post-infection. Aninhibitor of HCMV is identified by the reduction in titer of virus yieldin the presence, compared to the titer in the absence of compound. Inthis assay, the relative anti-HCMV activity of an inhibitor is typicallydetermined by calculating the IC₅₀ or IC₉₀ value, that is, the amount ofcompound required to reduce the virus yield by 50% or 90%, respectively.Table I describes IC₅₀ data for compounds tested against HCMV.

[1087] Microtiter Plate Assay.

[1088] Ninety-six well plate cultures of human foreskin fibroblasts areinfected in the presence of inhibitor compound with a HCMV recombinantmutant virus whose genome contains the prokaryotic beta-glucuronidasegene (Jefferson, R. A., S. M. Burgess, and D. Hirsh. 1986.Beta-glucuronidase from Escherichia coli as a gene fusion marker. Proc.Natl. Acad. Sci. USA 83:8447-8451) whose expression is controlled by aviral promoter. An example of such a virus is RV145 (Jones, T. R., V. P.Muzithras, and Y. Gluzman. 1991. Replacement mutagenesis of the humancytomegalovirus genome: US10 and US11 gene products are nonessential. J.Virol. 65:5860-5872). Since it is under the control of a viral promoter,beta-glucuronidase expression is an indirect indicator of growth andreplication of HCMV in this assay. At 96 hours post-infection, theinfected cell lysates are prepared (using 50 mM sodium phosphate [pH7.0]containing 0.1% Triton X-100 and 0.1% sarkosyl) and assayed forbeta-glucuronidase activity using a substrate for the enzyme which whencleaved yields either a product which can be measured colorimetricallyin a spectrophotometer or fluorescently in a microfluorimeter. Examplesof such substrates are p-nitrophenyl-beta-D-glucuronide andmethylumbelliferylglucuronide, respectively. The presence of anantiviral compound is indicated by the reduced expression of the HCMVgenome resident beta-glucuronidase gene, compared to the absence ofinhibitor. Thus, the generation of the chromophore or fluorophoreproduct in this assay is correspondingly reduced. Data from this assaygenerated using varying amounts of inhibitor compound is also used toestimate the IC₅₀ of an inhibitor compound.

HSV Antiviral (ELISA) Assay

[1089] Vero cells (ATCC #CCL-81) are plated on 96-well tissue cultureplates at 3.5×10⁴ cells per 100 μl tissue culture DMEM (Dulbecco'smodified Eagle media) supplemented with 2% fetal bovine serum (FBS) ineach well. After overnight incubation @37° C. (in 5% CO₂) and 30 minutesprior to infection with HSV-1 (multiplicity of infection equal to0.006), cells are either untreated, or treated with test compound(multiple concentrations) or reference standard drug control. Afterapproximately 24 hours post-infection incubation @ 37° C. (in 5% CO₂),cells are fixed for ELISA assay. The primary antibody is murine anti-HSVglycoprotein D monoclonal primary antibody and the secondary antibody isgoat anti-mouse IgG linked to B-galactosidase. Thus the extent of viralreplication is determined by assessing B-galactosidase activity byquantifying the generation of the 4-methyl. umbelliferone fluorescentcleavage product after addition of the methylumbelliferyl-β-D-galactoside (Sigma #M1633) substrate on amicrofluorimeter (365 nm for excitation and 450 nm for emission).Antiviral activity (IC₅₀) of the test compound is determined bycomparing the flourescence obtained in absence of compound to thatobtained in the presence of compound. Data is shown in Table I.

VZV Antiviral (ELISA) Assay

[1090] For the generation of stock VZV to be used in the assay, VZVstrain Ellen (ATCC #VR-1367) is used to infect human foreskin fibroblast(HFF) cells at low multiplicity (less than 0.1) and incubated overnightat 37° C. in 5% CO₂. After the overnight incubation, the mixture ofuninfected and VZV-infected HFF infected cells are then harvested andadded to each well of 96-well plates (3.5×10⁴ cells in 100 VI DMEMsupplemented with 2% FBS) which contain test compound or the referencestandard drug control (in 100 μl DMEM supplemented with 2% FBS perwell). These cells are incubated for three days at 37° C. in 5% CO, thenfixed for ELISA assay. The primary antibody is murine anti-VZVglycoprotein II monoclonal antibody (Applied Biosystems, Inc.#13-145-100) and the secondary antibody is goat anti-mouse IgG linked to8-galactosidase. Thus the extent of viral replication is determined byassessing 83-galactosidase activity by quantifying the generation of the4-methyl umbelliferone fluorescent cleavage product after addition ofthe methyl umbelliferyl-β-D-galactoside (Sigma #M1633) substrate on amicrofluorimeter (365 nm for excitation and 450 nm for emission).Antiviral activity (IC₅₀) of the test compound is determined bycomparing the flourescence obtained in absence of compound to thatobtained in the presence of compound. Data is shown in Table I. TABLE Idescribes IC₅₀ data for compounds tested against herpes viruses. IC₅₀IC₅₀ % inhibition IC₅₀ (ug/ml) (ug/ml) 10 ug/ml (ug/ml) Example HCMV HSVVZV VZV 283 7 0.6 17 >10 284 0.4 3 100 >15 289 >10 0.6 30 >10 498 0.14 614 >10 499 3 5 25 >10 506 >10 >10 68 >10 507 1.2 10 90 4 512 0.7 0.5 704 514 1.2 4 62 >10 515 >10 >10 30 >10 815 0.0024 >7.5 816 0.0015 >7.5817 0.001 >7.5 818 0.0022 >7.5 819 0.0022 >7.5 820 0.0013 3.4 8210.014 >7.5 822 0.05 >7.5 823 0.05 >7.5 824 0.004 3.20 825 0.003 6.12 8260.020 0.86 827 0.026 828 0.45 >7.5 829 0.08 >7.5

[1091] Thus, in accordance with the present invention, compounds of thepresent invention may be administered to a patient suffering from VZV,in an amount effective to inhibit the virus. Compounds of the presentinvention are thus useful to ameliorate to eliminate the symptoms of VZVinfections in mammals including, but not limited to humans.

[1092] Compounds of the invention may be administered to a patienteither neat or with a convention pharmaceutical carrier.

[1093] Applicable solid carriers can include one or more substanceswhich may also act as flavoring agents, lubricants, solubilizers,suspending agents, fillers, glidants, compression aids, binders ortablet-disintegrating agents or an encapsulating material. In powders,the carrier is a finely divided solid which is in admixture with the,finely divided active ingredient. In tablets, the active ingredient ismixed with a carrier having the necessary compression properties insuitable proportions and compacted in the shape and size desired. Thepowders and tablets preferably contain up to 99% of the activeingredient. Suitable solid carriers include, for example, calciumphosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch,gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose,polyvinylpyrrolidine, low melting waxes and ion exchange resins.

[1094] Liquid carriers may be used in preparing solutions, suspensions,emulsions, syrups and elixirs. The active ingredient of this inventioncan be dissolved or suspended in a pharmaceutically acceptable liquidcarrier such as water, an organic solvent, a mixture of both orpharmaceutically acceptable oils or fat. The liquid carrier can containother suitable pharmaceutical additives such as solubilizers,emulsifiers, buffers, preservatives, sweeteners, flavoring agents,suspending agents, thickening agents, colors, viscosity regulators,stabilizers or osmo-regulators. Suitable examples of liquid carriers fororal and parenteral administration include water (particularlycontaining additives as above e.g. cellulose derivatives, preferablysodium carboxymethyl cellulose solution), alcohols (including monohydricalcohols and polyhydric alcohols e.g. glycols) and their derivatives,and oils (e.g. fractionated coconut oil and arachis oil). For parenteraladministration the carrier can also be an oily ester such as ethyloleate and isopropyl myristate. Sterile liquid carriers are used insterile liquid form compositions for parenteral administration.

[1095] Liquid pharmaceutical compositions which are sterile solutions orsuspensions can be utilized by, for example, intramuscular,intraperitoneal or subcutaneous injection. Sterile solutions can also beadministered intravenously. Oral administration may be either liquid orsolid composition form.

[1096] Preferably the pharmaceutical composition is in unit dosage form,e.g. as tablets or capsules. In such form, the composition issub-divided in unit dose containing appropriate quantities of the activeingredient; the unit dosage forms can be packaged compositions, forexample packeted powders, vials, ampoules, prefilled syringes or sachetscontaining liquids. The unit dosage form can be, for example, a capsuleor tablet itself, or it can be the appropriate number of any suchcompositions in package form.

[1097] The therapeutically effective dosage to be used in the treatmentof CMV infection must be subjectively determined by the attendingphysician. The variables involved include the the condition, age andweight of the patient. The novel method of the invention for treatingCMV infection comprises administering to a subject, including humans, aneffective amount of at least one compound of Formula 1 or a non-toxic,pharmaceutically acceptable salt thereof. The compounds may beadministered orally, rectally, parenterally or topically to the skin andmucosa. The usual daily dose is depending on the specific compound,method of treatment and condition of the patient. The usual daily doseis 0.01-1000 mg/Kg for oral application, preferably 0.5-500 mg/Kg, and0.1-100 mg/Kg for parenteral application, preferably 0.5-50 mg/Kg.

What is claimed:
 1. A compound of the formula

R₁-R₅ are independently selected from hydrogen, alkyl of 1 to 6 carbonatoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms,perhaloalkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms,heterocycloalkyl of 3 to 10 carbon members, aryl, heteroaryl, halogen,—CN, —NO₂,—CO₂R₆, —COR₆, —OR₆, —SR₆, —SOR₆, —SO₂R₆, —CONR₇R₈,—NR₆N(R₇R₈), —N(R₇R₈) or W—Y—(CH)_(n)—Z; or R, and R, or R₃ and R₄,taken together form a 3 to 7 membered heterocycloalkyl or 3 to 7membered heteroaryl; R₆ and R7 are independently hydrogen, alkyl of 1 to6 carbon atoms, perhaloalkyl of 1 to 6 carbon atoms, or aryl; R₈ ishydrogen, alkyl of 1 to 6 carbon atoms, perhaloalkyl of 1 to 6 carbonatoms, cycloalkyl of 3 to 10 carbon atoms, heterocycloalkyl of 3 to 10members, aryl or heteroaryl, or R₇ and R₈, taken together may form a 3to 7 membered heterocycloalkyl; A is heteroaryl; W is O, NR₆, or isabsent; Y is —(CO)— or —(CO₂)—, or is absent; Z is alkyl of 1 to 4carbon atoms, —CN, —CO₂R₆, COR₆, —CONR₇R₈, —OCOR₆, —NR₆COR₇, —OCONR₆,—OR₆, —SR₆, —SOR₆, —SO₂R₆, SR6N(R7R8), —N(R₆R) or phenyl; G is aryl orheteroaryl; X is a bond, —NH, alkyl of 1 to 6 carbon atoms, alkenyl of 1to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, thioalkyl of 1 to 6carbon atoms, alkylamino of 1 to 6 carbon atoms, or (CH)J; J is alkyl of1 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, phenyl orbenzyl; and n is an integer from 1 to 6; or a pharmaceutical saltthereof.
 2. A compound of claim 1 wherein at least one of R₁-R₅ is nothydrogen.
 3. A compound of claim 1 wherein R₁-R₅ are, independentlyselected from hydrogen, alkoxy of 1 to 6 carbon atoms, perhaloalkyl of 1to 6 carbon atoms and halogen.
 4. A compound of claim 1 wherein X isCH(J) and J is alkyl of 1 to 6 carbon atoms.
 5. A compound of claim 4wherein J is methyl.
 6. A compound of claim 1 wherein A isunsubstituted.
 7. A compound of claim 1 wherein A is pyridinyl.
 8. Acompound of claim 1 wherein G is an unsubstituted 5 or 6 memberedheteroaryl.
 9. A compound of claim 8 wherein G is furyl, thiazoly, orthiadiazolyl.
 10. A compound of claim 8 wherein G is 2-furyl.
 11. Acompound of claim 8 wherein G is 1,2,3 thiadiazolyl.
 12. A compound ofclaim 8 wherein G is 1,3-thiazolyl.
 13. A compound of claim 1 wherein Gis phenyl.
 14. A compound of claim 1 wherein G is substituted phenyl.15. A compound of claim 14 wherein G is substituted with one or moresubstituents selected from halogen or alkoxy of 1 to 6 carbon atoms. 16.A compound of claim 1 wherein X is CH(J), J is methyl, A is pyridyl, andG is thiazolyl.
 17. A compound of claim 1 selected from:Furan-2-carboxylic acid{5-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-pyridin-2-yl}-amide,[1,2,3]Thiadiazole-4-carboxylic acid5-[3-{5-chloro-2,4-dimethoxy-phenyl)-thioureido]-pyridin-2-yl}-amide,Pyridine-2-carboxylic acid{5-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-pyridin-2-yl}-amide,Pyridine-2-carboxylic acid{6-[3-5-chloro-2,4-dimethoxy-phenyl)-thioureido]-pyridin-3-yl}-amide,Furan-2-carboxylic acid{6-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-pyridin-3-yl}-amide,[1,2,3]Thiadiazole-4-carboxylic acid{6-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-pyridin-3-yl}-amide,[1,2,3]Thiadiazole-4-carboxylic acid{5-[3-(3,5-dichloro-phenyl)-thioureido]-pyridin-2-yl}-amide,N-[5-[[[(5-Chloro-2,4-dimethoxyphenyl)amino]thioxomethyl]amino]-2-pyridinyl]-2-methylbenzamide,N-{5-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-pyridin-2-yl}-2-fluoro-benzamide,N-{6-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-pyridin-3-yl}-2-fluoro-benzamide,Furan-2-carboxylic acid{6-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-pyridin-3-yl}-amide,[1,2,3]Thiadiazole-4-carboxylic acid{6-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-pyridin-3-yl}-amide,[1,2,3]Thiadiazole-4-carboxylic acid{5-[3-(3,5-dichloro-phenyl)-thioureido]-pyridin-2-yl}-amide;N-[5-[[[(5-Chloro-2,4-dimethoxyphenyl)amino]thioxomethyl]amino]-2-pyridinyl]-2-methylbenzamide,N-{5-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-pyridin-2-yl}-2-fluoro-benzamide,N-{6-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-pyridin-3-yl}-2-fluoro-benzamide,N-(5-[({[3,5-bis(trifluoromethyl)benzyl]aminocarbothioyl)amino]-2-pyridinyl}-1,2,3-thiadiazole-4carboxamide,N-(5-{[({(1S)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}amino)carbothioyl]amino}-2-pyridinyl)-1,2,3-thiadiazole-4-carboxamide,N-(5-{[({(1 S)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}amino)carbothioyl]amino}-2-pyridinyl)-1,3-thiazole-4-carboxamide,N-(5-{[({1-[2-fluoro,-5-(trifluoromethyl)phenyl]ethyl}amino)carbothioyl]amino}-2-pyridinyl)-1,3-thiazole-4-carboxamide,N-(5-{[({1-[2-fluoro-4-(trifluoromethyl)phenyl]ethyl}amino)carbothioyl]amino}-2-pyridinyl)-1,3-thiazole-4-carboxamide,N-(5-{[({1-[3-fluoro-5-(trifluoromethyl)phenyl]ethyl}amino)carbothioyl]amino}-2-pyridinyl)-1,3-thiazole-4-carboxamide,N-(5-{[({(1S)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}amino)carbonyl]amino}-2-pyridinyl)-1,3-thiazole-4-carboxamide,N-{5-[({[1-(3-bromophenyl)ethyl]amino}carbothioyl)amino]-2-pyridinyl}-1,3-thiazole-4-carboxamide,N-{5-[({[1-(2-bromophenyl)ethyl]amino}carbothioyl)amino]-2-pyridinyl}-1,3-thiazole-4-carboxamide,N-(5-{[({1-[3-(trifluoromethyl)phenyl]ethyl}amino)carbothioyl]amino}-2-pyridinyl)-1,3-thiazole-4-carboxamide,N-(5-{[({1-[4-chloro-3-(trifluoromethyl)phenyl]ethyl}amino)carbothioyl]amino}-2-pyridinyl)-1,3-thiazole-4-carboxamide,N-(5-{[({[1-(4-chloro-3-fluorophenyl)ethyl]amino}carbothioyl)amino]-2-pyridinyl}-1,3-thiazole-4-carboxamide,N-{5-[({[1-(4-chloro-2-fluorophenyl)ethyl]amino}carbothioyl)amino]-2-pyridinyl}-1,3-thiazole-4-carboxamide,N-{6-[({[1-(4-fluorophenyl)ethyl]amino}carbothioyl)amino]-3-pyridinyl}-1,2,3-thiadiazole-4-carboxamide,and N-(6-{[({(1S)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}amino)carbothioyl]amino}-3-pyridinyl)-1,2,3-thiadiazole-4-carboxamide; andpharmaceutical salts thereof.
 18. A pharmaceutical compositioncomprising a compound of the formula

R₁-R₅ are independently selected from hydrogen, alkyl of 1 to 6 carbonatoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms,perhaloalkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms,heterocycloalkyl of 3 to 10 carbon members, aryl, heteroaryl, halogen,—CN, —NO₂, —CO₂R₆, —COR₆, —OR₆, —SR₆, —SOR₆, —SO₂R₆, —CONR₇R₈,—NR₆N(R₇R₈), —N(R₇R₈) or W—Y—(CH₂)_(n)—Z; or R₂ and R₃ or R₃ and R₄,taken together form a 3 to 7 membered heterocycloalkyl or 3 to 7membered heteroaryl; R₆ and R₇ are independently hydrogen, alkyl of 1 to6 carbon atoms, perhaloalkyl of 1 to 6 carbon atoms, or aryl; R₈ ishydrogen, alkyl of 1 to 6 carbon atoms, perhaloalkyl of 1 to 6 carbonatoms, cycloalkyl of 3 to 10 carbon atoms, heterocycloalkyl of 3 to 10members, aryl or heteroaryl, or R₇ and R₈, taken together may form a 3to 7 membered heterocycloalkyl; A is heteroaryl; W is O, NR₆, or isabsent; Y is —(CO)— or —(CO₂)—, or is absent; Z is alkyl of 1 to 4carbon atoms, —CN, —CO₂R₆, COR₆, —CONR₈, —OCOR₆, —NR₆COR₇,—OCONR₆,—OR₆,—SR₆,—SOR₆, —SO₂R₆, SR6N(R7R8), —N(R₇R₈) or phenyl; G isaryl or heteroaryl; X is a bond, —NH, alkyl of 1 to 6 carbon atoms,alkenyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, thioalkylof 1 to 6 carbon atoms, alkylamino of 1 to 6 carbon atoms, or (CH)J; Jis alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms,phenyl or benzyl; and n is an integer from 1 to 6; or a pharmaceuticalsalt thereof or a pharmaceutically acceptable carrier or diluent.
 19. Amethod of inhibiting the replication of a herpes virus comprisingcontacting a compound of the formula

wherein R₁-R₅ are independently selected from hydrogen, alkyl of 1 to 6carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbonatoms, perhaloalkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbonatoms, heterocycloalkyl of 3 to 10 carbon members, aryl, heteroaryl,halogen, —CN, —NO₂, —CO₂R₆, —COR₆, —OR₆, —SR₆, —SOR₆, —SO₂R₆, —CONR₇R₈,—NR₆N(R₇R₈), —N(R₇R₈) or W—Y—(CH₂)_(n)—Z; or R₂ and R, or R₃ and R₄,taken together form a 3 to 7 membered heterocycloalkyl or 3 to 7membered heteroaryl; R₆ and R₇ are independently hydrogen, alkyl of 1 to6 carbon atoms, perhaloalkyl of 1 to 6 carbon atoms, or aryl; R₈ ishydrogen, alkyl of 1 to 6 carbon atoms, perhaloalkyl of 1 to 6 carbonatoms, cycloalkyl of 3 to 10 carbon atoms, heterocycloalkyl of 3 to 10members, aryl or heteroaryl, or R7 and R₈, taken together may form a 3to 7 membered heterocycloalkyl; A is heteroaryl; W is O, NR₆, or isabsent; Y is —(CO)— or —(CO₂)—, or is absent; Z is alkyl of 1 to 4carbon atoms, —CN, —CO₂R₆, COR₆, —CONR₇R₈, —OCOR₆, —NR₆COR₇, —OCONR₆,—OR₆, —SR₆, —SOR₆, —SO₂R₆, SR6N(R7R8), —N(R₇R₈) or phenyl; G is aryl orheteroaryl; X is a bond, —NH, alkyl of 1 to 6 carbon atoms, alkenyl of 1to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, thioalkyl of 1 to 6carbon atoms, alkylamino of 1 to 6 carbon atoms, or (CH)J; J is alkyl of1 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, phenyl orbenzyl; and n is an integer from 1 to 6; or a pharmaceutical saltthereof, with a herpes virus.
 20. The method of claim 19 wherein theherpes virus is human cytomegalovirus.
 21. The method of claim 19wherein the herpes virus is herpes simplex virus.
 22. The method ofclaim 19 where the herpes virus is varicella zoster virus.
 23. Themethod of claim 22 wherein the varicella zoster virus is treated withsubstantially pure (S) optical isomer.
 24. A method of treating apatient suffering from a herpes virus infection comprising administeringto the patient a therapeutically effective amount of a compound havingthe formula.

R₁-R₅ are independently selected from hydrogen, alkyl of 1 to 6 carbonatoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms,perhaloalkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms,heterocycloalkyl of 3 to 10 carbon members, aryl, heteroaryl, halogen,—CN, —NO —CO₂R₆,—COR₆,—OR₆,—SR₆, —SOR₆, —SOR₂R₆, —CONR₇R₈, —NR₆N(R₇R₈),—N(R₇R₈) or W—Y—(CH₂)_(n)—Z; or R₂ and R₃ or R₃ and R₄, taken togetherform a 3 to 7 membered heterocycloalkyl or 3 to 7 membered heteroaryl;R₆ and R₇ are independently hydrogen, alkyl of 1 to 6 carbon atoms,perhaloalkyl of 1 to 6 carbon atoms, or aryl; R₈ is hydrogen, alkyl of 1to 6 carbon atoms, perhaloalkyl of 1 to 6 carbon atoms, cycloalkyl of 3to 10 carbon atoms, heterocycloalkyl of 3 to 10 members, aryl orheteroaryl, or R₇ and R₈, taken together may form a 3 to 7 memberedheterocycloalkyl; A is heteroaryl; W is O, NR₆, or is absent; Y is—(CO)— or —(CO₂)—, or is absent; Z is alkyl of 1 to 4 carbon atoms, —CN,—CO₂R₆, COR₆, —CONR 7R₈, —OCOR₆, —NR₆COR₇, —OCONR₆, —OR₆, —SR₆, —SOR₆,—SO₂R₆, SR6N(R7R8), —N(R₇R₈) or phenyl; G is aryl or heteroaryl; X is abond, —NH, alkyl of 1 to 6 carbon atoms, alkenyl of 1 to 6 carbon atoms,alkoxy of 1 to 6 carbon atoms, thioalkyl of 1 to 6 carbon atoms,alkylamino of 1 to 6 carbon atoms, or (CH)J; J is alkyl of 1 to 6 carbonatoms, cycloalkyl of 3 to 7 carbon atoms, phenyl or benzyl; and n is aninteger from 1 to 6; or a pharmaceutical salt thereof.
 25. The method ofclaim 24 wherein the herpes virus is human cytomegalovirus.
 26. Themethod of claim 24 wherein the herpes virus is herpes simplex virus. 27.The method of claim 24 where the herpes virus is varicella zoster virus.28. The method of claim 27 where the varicella zoster virus is treatedwith substantially pure (S) optical isomer.